Diagnosis of optically identifiable ophthalmic conditions

ABSTRACT

An apparatus for performing multiple procedures involving the eye. The apparatus includes a data collection apparatus and a data analysis module. The data collection apparatus for collecting a data set corresponding to at least a portion of an eye of a patient is configured to provide data indicative of at least two neurological disorders selected from the group consisting of glaucoma, macular degeneration, diabetic retinopathy, Parkinson&#39;s disease, Alzheimer&#39;s disease, dyslexia, multiple sclerosis, optic neuritis, LDS, head trauma, diabetes, and inappropriate responses to contrast sensitivity patterns. The data analysis module interrelates the data indicative of at least two neurological disorders to provide an interpretive result.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation patent application of, and claimspriority and benefit to, co-pending U.S. patent application Ser. No.12/505,193, that was filed on Jul. 17, 2009 and entitled “Apparatus AndMethod for Diagnosis of Optically Identifiable Ophthalmic Conditions”,which is a divisional continuation patent application of, and claimspriority and benefit to, U.S. patent application Ser. No. 11/224,774that was filed on Sep. 13, 2005, entitled “Apparatus And Method forDiagnosis of Optically Identifiable Ophthalmic Conditions”, and nowissued U.S. Pat. No. 7,575,321, which is a continuation-in-partapplication of, and claims the priority and benefit to, U.S. patentapplication Ser. No. 10/697,454 that was filed Oct. 30, 2003, entitled“Apparatus And Method for Diagnosis of Optically Identifiable OphthalmicConditions”, and now issued U.S. Pat. No. 7,708,403. The patentapplication is being concurrently filed with U.S. patent applicationSer. No. 12/794,053, entitled “Diagnosis of Optically IdentifiableOphthalmic Conditions”. All of the aforementioned patent applicationsand patents are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The invention relates to testing for physiological and neurologicalconditions in general and particularly to systems and methods thatemploy optical imaging of an eye and the responses of individuals tovisual stimuli.

BACKGROUND OF THE INVENTION

Numerous systems and methods are known for examining states of health ofeyes. For example, U.S. Pat. No. 5,065,767, issued Nov. 19, 1991 toMaddess, discloses a psychophysical method for diagnosing glaucoma thatemploys a time varying contrast pattern. Glaucoma may be indicated foran individual who displays a higher than normal contrast threshold forobserving the pattern. Maddess also discloses other tests for glaucomasuch as the well-known observation of a scotoma, measurement ofintraocular pressure, and assessment of color vision defects. U.S. Pat.No. 5,295,495, issued Mar. 24, 1994 to Maddess, discloses systems andmethods for diagnosing glaucoma using an individual's response tohorizontally moving stripe patterns, which is known as optokineticnystagmus (OKN). The spatially varying patterns may also varytemporally. In U.S. Pat. No. 5,539,482, issued Jul. 23, 1996 to James etal., additional systems and methods for diagnosing glaucoma usingspatial as well as temporal variations in contrast patterns aredisclosed. U.S. Pat. No. 5,912,723, issued Jun. 15, 1999 to Maddess,discloses systems and methods that use a plurality of spatially andtemporally varying contrast patterns to improve the methods disclosed inthe earlier patents. U.S. Pat. No. 6,315,414, issued Nov. 13, 2001 toMaddess et al., describes systems and methods for making a binocularassessment of possible damage to the optical nerve, optical radiationsand white matter of the visual brain indicative of various neurologicaldisorders by measuring responses to visual stimuli.

U.S. Pat. No. 6,068,377, issued May 30, 2000 to McKinnon et al.,describes systems and methods for testing for glaucoma using a frequencydoubling phenomenon produced by isoluminent color visual stimuli. Thedisclosure is similar to that of Maddess and co-workers, but usesdifferent, preferably complementary, frequencies of light having thesame luminosity as the visual probe signal.

U.S. Pat. Nos. 5,713,353 and 6,113,537 describe systems and methods fortesting for blood glucose level using light patterns that vary inintensity, color, rate of flicker, spatial contrast, detail content andor speed. The approach described involves measuring the response of aperson to one or more light pattern variations and deducing a bloodglucose level by comparing the data to calibration data.

Other disease conditions and their identification are described in apaper by S. Sokol, entitled “The visually evoked cortical potential inthe optic nerve and visual pathway disorders,” which was published inElectrophysiological testing in diseases of the retina, optic nerve, andvisual pathway, edited by G. A. Fishman, published by the AmericanAcademy of Opthalmology, of San Francisco, in 1990, Volume 2, Pages105-141. An article by Clark Tsai, entitled “Optic Nerve Head and NerveFiber Layer in Alzheimer's Disease,” which was published in Arch. ofOpthalmology, Vol. 107, February, 1991, states that large diameterneurons are damaged in Alzheimer's disease.

U.S. Pat. No. 5,474,081, issued Dec. 12, 1995 to Livingstone et al.,describes systems and methods for determining magnocellular defect anddyslexia by presenting temporally and spatially varying patterns, anddetecting visually evoked potentials (VEP) using an electrode assemblyin contact with the subject being tested.

U.S. Pat. No. 6,129,682, issued Oct. 10, 2000 to Borchert et al.,discloses systems and methods for non-invasively measuring intracranialpressure from measurements of an eye, using an imaging scan of theretina of an eye and a measurement of intraocular pressure. Theintraocular pressure is measured by standard ocular tonometry, which isa procedure that generally involves contact with the eye. U.S. Pat. Nos.5,830,139, 6,120,460, 6,123,668, 6,123,943, 6,312,393 and 6,423,001describe various systems and methods that involve mechanical contactwith an eye in order to perform various tests. Direct physical contactwith an eye involves potential discomfort and risk of injury throughinadvertent application of force or transfer of harmful chemical orbiological material to the eye. Direct physical contact with an eye isalso potentially threatening to some patients, especially those who areyoung or who may not fully understand the test that is being performed.

First Generation FDT Instrument

The Frequency Doubling Technique (hereinafter “FDT”) presents back-litflashed images viewed on a fixed, flat shielded screen in front of astationary subject. The FDT instrument is similar, but smaller, and theFDT test is substantially shorter in testing duration, as compared to avisual field instrument that tests peripheral and central vision. Visualfield testing is standard in all offices providing comprehensive eyeexams and treatment of eye disease. The FDT instrument uses sinusoidalgrating targets of low spatial frequency (as opposed to simple dots oflight in a traditional visual field test). The sinusoidal gratings arereversed (black to white, and white to black) at 25 Hz. The subjectperceives the targets as small striped areas in either central orperipheral vision. As with traditional visual field testing, subjectsare seated and have the chin and forehead positioned in a stabilizingrest support. Generally, subjects are tested monocularly. They fixate atarget directly in front of them and respond by pushing a button eachtime they see an image flashed anywhere in their visual field. Theinstrument records and retests areas based on the subject's responses. Acomputer program operating on a processor calculates reliability basedon fixation losses. The entire test takes less than two minutes per eye.The FDT does not require dilation of the subject's eyes. Therefore, itdoes not impair vision or the ability to function after the test isperformed. The test causes no discomfort. The FDT has received approvalfrom the Federal Drug Administration and has been in clinical use forover four years.

There is a need for systems and methods that will provide betterinformation about a larger number of possible conditions using a singletesting period, and that will disclose the initial levels of impairmentat accuracies that are not presently attainable, while avoiding to theextent possible mechanical contact with the test subject, especiallycontact with the eye. There is also a need for systems and methods thatcan be used by non-specialist medical practitioners to screen andevaluate patients without the necessity to first involve a specialistpractitioner.

SUMMARY OF THE INVENTION

The invention uses more than one observation selected from imagingmethods and responses (e.g., a “data set”) of a person to provide anassessment of a state of health or medical condition of the person. Theimages are obtained from any imaging method that provides imageinformation about a portion of an eye. The responses or data sets areobtained as the response of a person to a test that elicits voluntary orinvoluntary responses that provide information about a neurologicalstate or condition of the person. The invention combines or correlatesinformation from the more than one observation to provide theassessment.

In one aspect, the invention relates to a method of obtaining aninterpretive result relating to a condition of a person. The methodcomprises the steps of receiving at a testing venue a person whosecondition is to be evaluated; testing the person at the testing venuewith an apparatus having at least one imager for imaging at least aportion of an eye of the person and at least one data collectionapparatus for collecting from the eye a data set indicative of aneurological disorder, the testing comprises observing with theapparatus at least two disparate kinds of information selected from oneor more images and one or more data sets; and interrelating the at leasttwo disparate kinds of information selected from one or more images andone or more data sets to obtain the interpretive result relating to thecondition of the person.

In one embodiment, the at least one imager for imaging at least aportion of an eye of the person is configured to provide image datacomprises at least one image data type selected from the groupconsisting of data from ophthalmic images using confocal microscopydata, retinal polarimetry data, optical coherence tompography data,thermal image data, spectroscopic image data, refractometry data, andvisible image data. In one embodiment, the data set indicative of aneurological disorder is selected from the group consisting of dataindicative of a selected one of macular degeneration, diabeticretinopathy, Parkinson's disease, Alzheimer's disease, non-Alzheimer'sdementia, dyslexia, multiple sclerosis, optic neuritis, optical neuroma,ALS, head trauma, diabetes, and inappropriate responses to contrastsensitivity patterns. In one embodiment, the interpretive resultcomprises providing an indication of a selected one of normal health,the early (or onset) stage of the disease condition, and the developmentof the disease condition up to a fully presented disease condition.

In one embodiment, the method further comprises the step of recording ina memory at least one of the at least two disparate kinds of informationselected from one or more images and one or more data sets. In oneembodiment, the method further comprises the step of retrieving asinformation from the memory at least one of the at least two disparatekinds of information selected from one or more images and one or moredata sets. In one embodiment, the further comprises the step ofcomparing retrieved information with current information to monitor aselected one of a rate of evolution and an extent of evolution of adisease condition in the person.

In one embodiment, the method further comprises the step of applying astress to the person. In one embodiment, applying a stress to the personcomprises applying a stress selected from the group consisting of anintra ocular pressure variation, a blood pressure variation, an oxygenconcentration variation, performing exercise, a flashing light, anadministration of a drug, an administration of insulin, and anadministration of glucose. In one embodiment, the method furthercomprises the step of observing a response of the person to the stresson the person. In one embodiment, the method further comprises the stepof observing a time evolution of the response of the person to thestress on the person.

In one embodiment, the method further comprises the step of performing aselected one of displaying the interpretive result and reporting theinterpretive result. In one embodiment, the method further comprises thestep of receiving financial compensation for performing a selected oneof displaying the interpretive result and reporting the interpretiveresult.

In one embodiment, the method further comprises the step of receivingfinancial compensation for performing the testing.

In one embodiment, the interpretive result comprises providing anindication of a tendency to develop a disease condition.

In another aspect, the invention features a testing venue for testing acondition of a person. The testing venue comprises a venue wherein atest of a condition of a person is performed; an apparatus located atthe venue having at least one imager for imaging at least a portion ofan eye of the person and at least one data collection apparatus forcollecting from the eye a data set indicative of a neurologicaldisorder, the apparatus configured to obtain at least two disparatekinds of information selected from one or more images and one or moredata sets with the apparatus; and a data analysis module that receivesand interrelates the at least two disparate kinds of informationselected from one or more images and one or more data sets to providethe interpretive result relating to the condition of the person.

In one embodiment, the at least one imager for imaging at least aportion of an eye of the person is configured to provide image datacomprises at least one image data type selected from the groupconsisting of data from ophthalmic images using confocal microscopydata, retinal polarimetry data, optical coherence tompography data,thermal image data, spectroscopic image data, refractometry data, andvisible image data. In one embodiment, the data set indicative of aneurological disorder is selected from the group consisting of dataindicative of a selected one of macular degeneration, diabeticretinopathy, Parkinson's disease, Alzheimer's disease, non-Alzheimer'sdementia, dyslexia, multiple sclerosis, optic neuritis, optical neuroma,ALS, head trauma, diabetes, and inappropriate responses to contrastsensitivity patterns.

In one embodiment, the testing venue further comprises a memory forrecording at least one of the at least two disparate kinds ofinformation selected from one or more images and one or more data setswith the apparatus. In one embodiment, at least one of the at least twodisparate kinds of information selected from one or more images and oneor more data sets recorded in the memory can be retrieved asinformation. In one embodiment, the data analysis module is configuredto compare retrieved information from the memory with currentinformation to monitor a selected one of a rate of evolution and anextent of evolution of a disease condition in the person.

In one embodiment, the testing venue further comprises a display fordisplaying the interpretive result. In one embodiment, the testing venuefurther comprises a reporting module for reporting the interpretiveresult. In one embodiment, the apparatus having at least one imager forimaging at least a portion of an eye of the person and at least one datacollection apparatus for collecting from the eye a data set indicativeof a neurological disorder is configured to observe a response to astress applied to the person. In one embodiment, a stress applied to theperson comprises a stress selected from the group consisting of an intraocular pressure variation, a blood pressure variation, an oxygenconcentration variation, performing exercise, a flashing light, anadministration of a drug, an administration of insulin, and anadministration of glucose. In one embodiment, the apparatus having atleast one imager for imaging at least a portion of an eye of the personand at least one data collection apparatus for collecting from the eye adata set indicative of a neurological disorder is configured to observea time evolution of the response of the person to the applied stress. Inone embodiment, the interpretive result comprises an indication of aselected one of normal health, the early (or onset) stage of the diseasecondition, and the development of the disease condition up to a fullypresented disease condition. In one embodiment, the interpretive resultcomprises an indication of a tendency to develop a disease condition.

In yet a further aspect, the invention relates to an apparatus forobtaining an interpretive result relating to a condition of a person.The apparatus comprises at least one imager for imaging at least aportion of an eye of the person configured to observe one or moreimages; at least one data collection apparatus for collecting from theeye a data set indicative of a neurological disorder; an analysis modulecomprises a programmable processor and computer software recorded on acomputer-readable medium. The computer software when operating performsthe steps of interrelating at least two disparate kinds of informationselected from one or more images and one or more data sets to attempt toobtain an interpretive result relating to the condition of the person;(a) in the event that the attempt to obtain an interpretive resultrelating to the condition of the person provides a result representing astate of normal health, recording the result and terminating theanalysis; and (b) in the event that the attempt to obtain aninterpretive result relating to the condition of the person provides aresult representing a state of health that is not normal health,attempting to distinguish a condition represented by the state of healththat is not normal health; (b)(1) in the event that the attempt todistinguish the condition represented by the state of health that is notnormal health is successful, reporting an interpretive result of thecondition and terminating the analysis.

In one embodiment, the computer software when operating further performsthe step of (b)(2) in the event that the attempt to distinguish thecondition represented by the state of health that is not normal healthis unsuccessful, reporting the failure to distinguish a condition.

In one embodiment, wherein the computer software when operating furtherperforms the step of (b)(3) optionally, prompting a user of theapparatus to provide additional information about the person.

In one embodiment, wherein the computer software when operating furtherperforms the step of (c) upon provision of the additional informationabout the person, iteratively repeating the interrelating step and, asappropriate, each of conditional steps (b), (b)(1), (b)(2), (b)(3) andthis step (c) using the additional information provided in response tothe prompting step (b)(3) in addition to the at least two disparatekinds of information selected from one or more images and one or moredata sets to attempt to obtain an interpretive result relating to thecondition of the person until the first to occur of: the analysis isterminated according to step (b)(1); the iteratively repeating step isperformed a predetermined number of times without distinguishing thecondition represented by the state of health that is not normal health;the iteratively repeating step is performed until a specified period oftime elapses without distinguishing the condition represented by thestate of health that is not normal health; and a user of the apparatusdetermines that the analysis should be terminated, and intervenes toterminate the analysis.

In one embodiment, the additional information about the person comprisesat least a selected one of collecting an additional image and collectingan additional data set. In one embodiment, the additional informationabout the person comprises additional information from a magneticresonance imaging (MRI) test. In one embodiment, the MRI test comprisesa structural MRI test. In one embodiment, the MRI test comprises afunctional MRI test. In one embodiment, the additional information aboutthe person comprises patient history data. In one embodiment, theadditional information about the person comprises vital signs data. Inone embodiment, the additional information about the person comprisesadditional information from a positron emission tomography (PET) test.In one embodiment, the PET test comprises an FDG-PET glucosedetermination. In one embodiment, the PET test comprises a C-PK11195-PETtest. In one embodiment, the additional information about the personcomprises additional information from a brain biopsy. In one embodiment,the additional information about the person comprises additionalinformation from a cognitive impairment test. In one embodiment, theorder of performs the steps of obtaining an image, obtaining a data setindicative of a neurological disorder, and obtaining the additionalinformation about the person is not critical, and may be performed inany order that is convenient.

In one embodiment, when the computer software is operating, step (b)(1)is performed at least a second time to attempt to distinguish a secondstate of health that is not normal health different from the reportedstate of health that is not normal health. In one embodiment, when thecomputer software is operating, optionally, in step (a) the apparatusprovides information relating to state of normal health to a user of theapparatus. In one embodiment, when the computer software is operating,optionally, in step (b)(1), the apparatus records the interpretiveresult of the condition. In one embodiment, the at least one imager forimaging at least a portion of an eye of the person is configured toprovide image data comprises at least one image data type selected fromthe group consisting of data from ophthalmic images using confocalmicroscopy data, retinal polarimetry data, optical coherence tompographydata, thermal image data, spectroscopic image data, refractometry data,and visible image data. In one embodiment, the data set indicative of aneurological disorder is selected from the group consisting of dataindicative of a selected one of macular degeneration, diabeticretinopathy, Parkinson's disease, Alzheimer's disease, non-Alzheimer'sdementia, dyslexia, multiple sclerosis, optic neuritis, optical neuroma,ALS, head trauma, diabetes, and inappropriate responses to contrastsensitivity patterns. In one embodiment, the interpretive resultcomprises an indication of a selected one of normal health, the early(or onset) stage of the disease condition, and the development of thedisease condition up to a fully presented disease condition. In oneembodiment, the computer software when operating further performs thestep of recording in a memory at least one of the at least two disparatekinds of information selected from one or more images and one or moredata sets. In one embodiment, the computer software when operatingfurther performs the step of retrieving as information from the memoryat least one of the at least two disparate kinds of information selectedfrom one or more images and one or more data sets. In one embodiment,when the computer software when operating further performs the step ofcomparing retrieved information with current information to monitor aselected one of a rate of evolution and an extent of evolution of adisease condition in the person. In one embodiment, the computersoftware when operating further performs the step of applying a stressto the person. In one embodiment, applying a stress to the personcomprises applying a stress selected from the group consisting of anintra ocular pressure variation, a blood pressure variation, an oxygenconcentration variation, performing exercise, a flashing light, anadministration of a drug, an administration of insulin, and anadministration of glucose. In one embodiment, the computer software whenoperating further performs the step of observing a response of theperson to the stress on the person. In one embodiment, the computersoftware when operating further performs the step of observing a timeevolution of the response of the person to the stress on the person. Inone embodiment, the computer software when operating further performsthe step of performing a selected one of displaying the interpretiveresult and reporting the interpretive result. In one embodiment, theinterpretive result comprises an indication of a tendency to develop adisease condition. In one embodiment, the computer software whenoperating repeats its operation for data relating to a second eye of theperson to determine a condition of health of the person. In oneembodiment, the condition of health of the person obtained from datafrom one of the first eye of the person and the second eye of the personis used as a baseline condition for a later testing of the other of thefirst eye of the person and the second eye of the person.

In an additional aspect, the invention features an apparatus forobtaining an interpretive result relating to a condition of a person.The apparatus comprises at least one data collection apparatus forcollecting from the eye a data set indicative of a neurologicaldisorder; an analysis module comprising a programmable processor andcomputer software recorded on a computer-readable medium, the computersoftware when operating performing the steps of: attempting to obtainfrom the one or more data sets an interpretive result relating to thecondition of the person; (a) in the event that the attempt to obtain aninterpretive result relating to the condition of the person provides aresult representing a state of normal health, recording the result andterminating the analysis; and (b) in the event that the attempt toobtain an interpretive result relating to the condition of the personprovides a result representing a state of health that is not normalhealth, attempting to distinguish a condition represented by the stateof health that is not normal health; (b)(1) in the event that theattempt to distinguish the condition represented by the state of healththat is not normal health is successful, reporting an interpretiveresult of the condition and terminating the analysis.

In one embodiment, the computer software when operating further performsthe step of: (b)(2) in the event that the attempt to distinguish thecondition represented by the state of health that is not normal healthis unsuccessful, reporting the failure to distinguish a condition. Inone embodiment, the computer software when operating further performsthe step of: (b)(3) optionally, prompting a user of the apparatus toprovide additional information about the person. In one embodiment, thecomputer software when operating further performs the step of: (c) uponprovision of the additional information about the person, iterativelyrepeating the interrelating step and, as appropriate, each ofconditional steps (b), (b)(1), (b)(2), (b)(3) and this step (c) usingthe additional information provided in response to the prompting step(b)(3) in addition to the one or more data sets to attempt to obtain aninterpretive result relating to the condition of the person until thefirst to occur of: the analysis is terminated according to step (b)(1);the iteratively repeating step is performed a predetermined number oftimes without distinguishing the condition represented by the state ofhealth that is not normal health; the iteratively repeating step isperformed until a specified period of time elapses withoutdistinguishing the condition represented by the state of health that isnot normal health; and a user of the apparatus determines that theanalysis should be terminated, and intervenes to terminate the analysis.

In one embodiment, the additional information about the person comprisescollecting an additional data set. In one embodiment, the additionalinformation about the person comprises additional information from amagnetic resonance imaging (MRI) test the MRI test comprises astructural MRI test. In one embodiment, the MRI test comprises afunctional MRI test. In one embodiment, the additional information aboutthe person comprises patient history data. In one embodiment, theadditional information about the person comprises vital signs data. Inone embodiment, the additional information about the person comprisesadditional information from a positron emission tomography (PET) test.In one embodiment, the PET test comprises an FDG-PET glucosedetermination. In one embodiment, the PET test comprises a C-PK11195-PETtest. In one embodiment, the additional information about the personcomprises additional information from a brain biopsy. In one embodiment,the additional information about the person comprises additionalinformation from a cognitive impairment test. In one embodiment, theorder of performing the steps of obtaining a data set indicative of aneurological disorder and obtaining the additional information about theperson is not critical, and may be performed in any order that isconvenient. In one embodiment, when the computer software is operating,step (b)(1) is performed at least a second time to attempt todistinguish a second state of health that is not normal health differentfrom the reported state of health that is not normal health. In oneembodiment, when the computer software is operating, optionally, in step(a) the apparatus provides information relating to state of normalhealth to a user of the apparatus. In one embodiment, when the computersoftware is operating, optionally, in step (b)(1), the apparatus recordsthe interpretive result of the condition. In one embodiment, the dataset indicative of a neurological disorder is selected from the groupconsisting of data indicative of a selected one of macular degeneration,diabetic retinopathy, Parkinson's disease, Alzheimer's disease,non-Alzheimer's dementia, dyslexia, multiple sclerosis, optic neuritis,optical neuroma, ALS, head trauma, diabetes, and inappropriate responsesto contrast sensitivity patterns. In one embodiment, the interpretiveresult comprises an indication of a selected one of normal health, theearly (or onset) stage of the disease condition, and the development ofthe disease condition up to a fully presented disease condition. In oneembodiment, the computer software when operating further performs thestep of recording in a memory at least one or more data sets. In oneembodiment, the computer software when operating further performs thestep of retrieving as information from the memory at least one or moredata sets. In one embodiment, the computer software when operatingfurther performs the step of comparing retrieved information withcurrent information to monitor a selected one of a rate of evolution andan extent of evolution of a disease condition in the person. In oneembodiment, the computer software when operating further performs thestep of applying a stress to the person. In one embodiment, applying astress to the person comprises applying a stress selected from the groupconsisting of an intra ocular pressure variation, a blood pressurevariation, an oxygen concentration variation, performing exercise, aflashing light, an administration of a drug, an administration ofinsulin, and an administration of glucose. In one embodiment, thecomputer software when operating further performs the step of observinga response of the person to the stress on the person. In one embodiment,the computer software when operating further performs the step ofobserving a time evolution of the response of the person to the stresson the person. In one embodiment, the computer software when operatingfurther performs the step of performing a selected one of displaying theinterpretive result and reporting the interpretive result. In oneembodiment, the interpretive result comprises an indication of atendency to develop a disease condition. In one embodiment, the computersoftware when operating repeats its operation for data relating to asecond eye of the person to determine a condition of health of theperson. In one embodiment, the condition of health of the personobtained from data from one of the first eye of the person and thesecond eye of the person is used as a baseline condition for a latertesting of the other of the first eye of the person and the second eyeof the person. In one embodiment, the condition of health of the personis obtained from data relating to both the first eye of the person andthe second eye of the person.

The foregoing and other objects, aspects, features, and advantages ofthe invention will become more apparent from the following descriptionand from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The objects and features of the invention can be better understood withreference to the drawings described below, and the claims. The drawingsare not necessarily to scale, emphasis instead generally being placedupon illustrating the principles of the invention. In the drawings, likenumerals are used to indicate like parts throughout the various views.

FIG. 1A is a prior art diagram showing some of the physiology of the eyeand the brain in humans;

FIG. 1B depicts a prior art cross sectional diagram showing a feedbackloop from the visual cortex to the LGN;

FIG. 2 is a schematic representation of an exemplary apparatus suitablefor use according to the invention;

FIG. 3A shows a schematic diagram of the disposition of an eyemonitoring device relative to an eye of a person being tested accordingto the invention;

FIG. 3B shows a diagram that depicts the interrelationship among thefeatures of an eye of a person being tested, and the areas of the eyesensed by two sensors, according to the invention;

FIG. 3C shows a diagram that depicts the interrelationship between thefeatures of an eye of a person being tested, and the areas of the eyesensed by one sensor, according to the invention;

FIG. 3D shows a diagram that depicts a test pattern and a fixationsignal that is useful for fixating an eye of a person being tested whenone sensor is employed in the eye monitoring device, according to theinvention;

FIG. 4 is a flow chart showing the steps in the operation of theinstrument of the invention, or alternatively, showing theinterrelationships among the modules comprising apparatus according tothe invention;

FIG. 5 is a diagram that shows components of a superposition moduleaccording to the invention;

FIG. 6 is a diagram showing a region of frequency space having bothtemporal and spatial frequency variations, and indicating a typicalperson's reaction thereto, as is known in the prior art;

FIGS. 7A and 7B are drawings that depict a display space that issegmented and includes an illustrative contrast pattern, as is known inthe prior art;

FIGS. 8A, 8B and 8C are diagrams that show the relationship between animage and a data set, two images taken at different times, and a seriesof images, false color data representations, and data sets,respectively, according to principles of the invention;

FIG. 9 is a schematic showing the relationship among superimposed imagesand/or data sets, according to principles of the invention;

FIG. 10 shows a hand-held apparatus that measures a person's visualcontrast sensitivity according to principles of the invention;

FIG. 11 is a flow chart showing the steps in a measurement process,according to principles of the invention;

FIG. 12 is a diagram showing the feedback loop associated with theretina, the LGN and the VC; and

FIGS. 13A-13B are diagrams showing the time evolution of response tostimuli using several testing procedures.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides systems and methods for determining a wide rangeof possible medical conditions, including normal health, the early (oronset) stage of a disease condition, and the development of the diseasecondition up to a fully presented disease conditions (e.g., diagnosis,staging, and monitoring). The invention provides the ability to diagnosethe severity of various disease conditions. By application of themethods of the invention over time, one can monitor the rate and extentof evolution of various disease conditions in a particular individual.

The invention uses a combination of two or more observations, which caninclude an image of at least a portion of an eye of a patient, and adata set corresponding to a response from at least a portion of an eyeof a patient. The two or more observations can comprise two images, animage and a data set, or two data sets. Images and data sets will bereferred to generally as information, which should be understood asnecessary to mean either images or data sets or both. The images includevisualization of a portion of an eye, and can include ophthalmic imagesusing confocal microscopy data, retinal polarimetry data, opticalcoherence tompography data, thermal image data, spectroscopic imagedata, refractometry data, and visible image data. The data sets includedata that is indicative of neurological disorders. For example, theneurological disorders include glaucoma, macular degeneration, diabeticretinopathy, Parkinson's disease, Alzheimer's disease, dyslexia,multiple sclerosis, optic neuritis, and inappropriate responses tocontrast sensitivity patterns. In some embodiments, the images arevisible images that include color fundus photography and black and whitefluorescein angiography.

The functional deficits of glaucoma and Alzheimer's Disease (hereinafter“AD”) include loss in low spatial frequency ranges in contrastsensitivity, and are similar in both diseases. Glaucoma, unlike AD,involves losses of optic nerve fiber layer originating in the retina. Atpresent, the only definitive diagnosis of AD involves identifyingamyloid plaques and neuro-fibrillary tangles in the neurons of thecortex by microscopic analysis of brain tissue. The invasive nature ofthe test necessitates that the test be performed after death. A testspecific for low spatial frequency deficits, as is available fordiagnosing glaucoma, would be useful in measuring similar deficits inAD. The Frequency Doubling Technique (hereinafter “FDT”), unlike manyother tests of visual function, does not require a high degree ofconcentration or of cognition. Because FDT takes only two minutes toadminister to both eyes, it is appropriate for subjects who havedifficulty concentrating for long periods.

Visual Deficits and Cognitive Function

Visual dysfunction appears to be a strong predictor of cognitivedysfunction in subjects with AD. Pattern masking has been found to be agood predictor of cognitive performance in numerous standard cognitivetests. The tests found to correlate with pattern masking includedGollin, Stroop-Work, WAIS-PA, Stroop-Color, Geo-Complex Copy,Stroop-Mixed and RCPM. Losses in contrast sensitivity at the lowestspatial frequency also was predictive of cognitive losses in the seventests. AD subjects have abnormal word reading thresholds correspondingto their severity of cognitive impairment and reduced contrastsensitivity in all spatial frequencies as compared to normal subjects.

Review of the Physiology of Vision

The visual system is believed to be made up of two parallel pathways:the M pathway and the P pathway. The pathways have individualizedfunction. There are a total of approximately 160 million rod and conecells in the normal eye. There are approximately 1.2 million ganglioncells (M and P cells) in the normal eye. The magnocellular or M pathway(comprising M cells) is sensitive to contrast sensitivity and motion. Mcells comprise both My cells (usually associated with contrastsensitivity) and Mx cells (usually associated with motion). There areestimated to be approximately 12,000 cells of the My type in the normaleye. The magnocellular M system has high contrast gain and saturates atrelatively low contrasts. The parvocellular or P pathway (comprising Pcells) is specialized for processing color and form. The parvocellular Psystem has a low contrast grain and more linear contrast visual stimuli.Losses specific to the M pathway have been identified in subjects withAD even in brain areas devoid of plaques and neurofibriallary tangles.The M pathway shows signs of significant cell loss in AD subjects. Instudies of primates, lesions have been found in the magnocellular layersof the lateral geniculate nucleus that does not impact contrastsensitivity for stationary gratings. However, such lesions do impactsensitivity for events involving motion or high temporal content. It hasbeen found in primates that lesions identified in the parvocellularlayers of the lateral geniculate nucleus (LGN) impacted contrastsensitivity for stationary or low temporal content events.

Review of the Pathology of Glaucoma

Glaucoma is a disease that is categorized by increasing internal eyepressure on the optic nerve. The compression of the nerve causes nervefiber morbidity and eventually cell loss. It is believed that the Mganglion cells of the visual system are impacted to a greater extentthan the P cells in glaucoma. M cells are fewer in number, have largeraxon diameter and larger receptive fields. Measurements of the visualfield, measurements of intraocular pressure and observation of changesin the nerve fiber layer and optic disc are utilized to diagnosis andmanage glaucoma. In glaucoma, the location of optic nerve change andpallor corresponds to location and density of visual field loss. Newtechnologies that detect image losses in the nerve fiber layer may havethe ability to detect glaucoma damage prior to the appearance ofmeasurable visual field losses.

Contrast sensitivity function is frequently reduced in glaucoma. Thereis a high correlation of low spatial frequency contrast sensitivity lossand the mean visual field loss in glaucoma. Higher rates of glaucomahave been found among patients with AD compared to a control group. Thediagnosis of glaucoma was based on the visual field defects or opticnerve cupping. Higher rates of glaucoma have also been found amongpatient's diagnosed with Parkinson's disease.

Visual field loss is a definitive sign of glaucoma and loss in visualfield correlates with loss in contrast sensitivity. The appearance ofoptic nerve fiber loss detected either by observation of the fundus ofthe eye or by the application of newer technologies also correlates withvisual field losses. The technology of the present invention may detectlosses in visual field at earlier stages than the traditionalinstrumentation of visual field loss can measure the losses. Theconclusion that optic nerve appearance and loss in the nerve fiber layerwould correlate with loss in contrast sensitivity is a reasonable one inthe case of glaucoma. Other diseases that have losses in contrastsensitivity also have losses in the nerve fiber layer and changes inoptic nerve appearance.

Frequency Doubling Technology and Glaucoma

FDT has been shown to detect glaucomatous changes at earlier stages thanare detected with stereophotographs, and has better sensitivity andspecificity than motion-automated perimetry. FDT is a better predictorof progressive field loss as measured by standard automated perimetrythan pattern electroretinography in a population of chronic open angleglaucoma. FDT is useful for detection of early glaucomatous visual fielddamage as compared to a Humphrey Field Analyzer and a high passresolution perimeter.

In the FDT instrument, the sinusoidal gratings are reversed (black towhite, and white to black) at 25 Hz. This stimulates the My ganglioncells. The contrast between the light and dark lines in the sinusoidalgrating targets is changed in order to determine a threshold ofperception of the target which is related to the healthy My typeganglion cells of the retina. A standard visual field test stimulatesall ganglion cell types. It is believed that the My cells are the firstganglion cells to die in glaucoma. Therefore, FDT provides earlierdetection of glaucoma. Subjects with AD have reductions in low spatialfrequency, the same function that the FDT tests. The same cells may beimpacted by AD compared to glaucoma, but the mechanism of cell deathdiffers.

Review of the Pathology of AD

There has long been controversy as to the primary cause of AD visualsymptoms. It is well documented that there are contrast sensitivityreductions, in particular at low spatial frequencies, in AD. Abnormalvisual perception and abnormal visuospatial processing are common withpatients diagnosed as having AD.

AD is a progressive degenerative disease of the brain leading tosenility and dementia. It is known to affect millions of people and thenumbers are rapidly growing. There are numerous forms of dementia, ADbeing only one, albeit the most devastating. Cognitive questionnaires donot accurately separate AD from other forms of dementia.

Numerous pharmaceutical companies are working on treatments for AD thatwill slow the progression and, in some cases, reverse the effects of AD.What is needed is a definitive, non-invasive test for AD prior to death.

AD is a large diameter neuron disease (Tsai 1991). Some researchers havefound microscopic amyloid plaques on retinal ganglion cells, but not inall cases, and not at all stages of the disease. Sadun (1990) found lossin M-type retinal ganglion cells, contrast sensitivity, and visualfields in the absence of plaques or tangles, but other researchers wereunable to reproduce these findings, suggesting that there is aprogression in the disease with varying symptoms. Most researchers agreethat amyloid plagues and tangles on cortical neurons is definitive ofAD. Because a longitudinal study on suspect AD patients is impossibledue to the invasiveness of the procedure, the progression of AD is notunderstood in detail.

Documentation of Retinal Ganglion

The degeneration in the retinal ganglion cells (RGC) of patients withAlzheimer's Disease was identified using histopatholic measure. Sadunfound degeneration of the retinal ganglion cells and axonal degenerationupon examining the retro bulbar optic nerves. There was a greaterfrequency of degeneration the more posterior the nerve was located. Apossible implication is that the retinal ganglion cell loss may besecondary to retrograde axonal degeneration.

Nerve Fiber Layer Analysis

A significant reduction in nerve fiber thickness in AD subjects comparedto normal subjects has been observed using OCT Humphreys.

The present invention provides novel systems and methods fornon-invasively diagnosing and tracking AD, based on a new theory of theprogression of AD. In one aspect of the theory, the optic nerves are anextension of the brain and therefore provide a window to the workings ofthe brain. In one embodiment, the Welch Allyn Frequency DoubledTechnology (FDT) visual field exam isolates retinal ganglion cells ofthe My type. These cells are associated with contrast sensitivity. Dueto their large diameter, they are generally, though not universally,believed to be some of the first cells to die in glaucoma. Presumably,the ganglion cells are damaged by an ischemic effect when passing thoughbent lamina cribrosa as a result of elevated intra-ocular pressure(IOP).

FDT has become the gold standard for early diagnosis and tracking ofglaucoma. Anecdotally, FDT has produced false positive diagnoses ofglaucoma, when subsequent analysis indicated diagnoses of tumor, maculardegeneration, diabetic retinopathy, multiple sclerosis, and otherneurological diseases.

In addition, various researchers have suggested that glaucomatous damagemay extend beyond the retinal ganglion cells into the lateral geniculatenucleus (LGN) and the visual cortex, and that the frequency doubledillusion may be mediated by a cortical loss of temporal phasediscrimination, thus again suggesting that neuron involvement is notlimited to ganglion cells.

FIG. 1A is a prior art diagram showing some of the physiology of the eyeand the brain in humans. FIG. 1B is a prior art cross sectional diagramshowing a feedback loop from the visual cortex to the LGN. In fact,approximately 80% of the axons feeding the LGN come from the visualcortex, while approximately 20% come from the retina.

Clinical evaluations are currently underway to determine the efficacy ofusing FDT to diagnose and track AD. One unanswered question is whetherFDT should be optimized to increase sensitivity and specificity.Although My cells are likely involved in AD, other forms of ganglioncells are also likely involved, such as Mx cells and P cells. Thus, theFDT zone shapes and sizes, spatial frequency, and temporal frequency maybe optimized to isolate different forms of ganglion cells and theirinteraction with feedback neurons from the visual cortex. At earlystages of the disease, plaques and tangles likely form in the visualcortex, thus sending an abnormal feedback to the LGN. This corticofugalfeedback affects the signals from the retina leading through the LGN tothe visual cortex. The result is an abnormal FDT finding. This effectmay or may not be associated with ganglion cell damage caused by atrophyat a given stage in the disease. The exact etiology will only be knownfor certain after cross-sectional and longitudinal clinical evaluationsare performed with subsequent histological analysis of the neurons. Themechanism for ganglion cells loss will likely differ from glaucoma inthat there need not be elevated IOP in AD.

Similarly, it is believed that other neurological disorders (such asmacular degeneration, diabetic retinopathy, optic neuritis,pappilledema, anterior ischemic optic neuropathy, and tumor) can bediagnosed and tracked by optimizing FDT (A Primer for Frequency DoublingTechnology, Johnson, 1998). AD and Parkinson's were not mentioned inthis product literature and are the subject of this treatise and latestinvention. An improved FDT technology, hereinafter FDT2, may be abetter, though slower, test for AD in that there are significantlysmaller interrogated areas than in the original FDT, thus leading todetection of loss at an earlier stage and more accurate tracking of AD.FDT2 can achieve resolution that is impossible with FDT, therebyproviding results that could not have been provided heretofore.

It is believed that at some point before the disease process hasadvanced to the stage where AD can be diagnosed using present daymethods, functional vision losses associated with AD becomes apparent inthe optic nerve, nerve fiber layer and retina. In one embodiment, theretina includes the peripheral retina. A variety of nerve fiber imagingtechniques and photographic techniques have demonstrated changes in theoptic nerve of subjects with AD. However, subjective testing relying onvisual fields and perimetry techniques prove unreliable in AD subjectsbecause of poor attentive skills. The FDT2 is a modified visual fieldtest of short duration. Additionally, low spatial frequency targets areused to sample test areas. This FDT2 instrument has the ability tomeasure field losses in AD subjects as well as localize retinal areasexhibiting low spatial frequency deficits.

Studies of the visual symptoms of AD findings observed in brain lesionshave shown that damage occurs in the visual association cortex and othercortical areas, as well as the primary visual cortex.

It is believed that at some point other than early in the diseaseprocess, losses associated with AD become apparent in the optic nerveand nerve fiber layer. Because it is a low spatial frequency test, theFDT will pick up such losses unlike other subjective testing such astraditional visual field techniques. The source of degeneration in thevisual system does not likely originate at the level of the retinalganglion cells. However, it seems these tissues are not spared in AD. Ithas long been demonstrated that pathologies originating in the higherareas of brain function eventually appear as pathology to the optic discand nerve fiber layer. It has been shown by means of stereo photos thatloss in the optic disc and nerve fiber layer are measurable in AD atsome stage.

There is evidence that there are right and left field advantages forsome visual functions. Because the FDT is a test of function in manyways similar to a standard visual field, it is possible to test splitvisual fields and therefore isolate in each eye right retinal functionand left retinal function. It is also possible to compare the functionof the right eye to the function of the left eye.

Histopathology studies of the optic nerve of subjects with AD werethought to show axonal degeneration originating from the retina. Thereis a loss of both large and small diameter ganglion cell layer neurons.These studies concluded there is a greater drop out of the largerneurons which project to the M layers of the lateral geniculate nucleus.Based on studies of primate retina and visual function, if there is aloss of cells along the M pathway, it would be expected that there wouldbe reductions in the ability to perceive motion or high temporal contentevents. Several studies of AD subjects have reported this. Indirectcomparisons of losses in both the P channels and the M channels showedthat the M channel function deteriorates at a greater rate than the Pchannel function in AD.

The Present Invention

It is believed that the optic nerves, as direct and intimate extensionsof the brain, are likely to be among the earliest nerves to exhibitchanges associated with various neurological disorders. It is believedthat these neurological disorders are observable by imaging the eye andmeasuring changes (or deviations) therein from what is considerednormal, as well as in neurological responses that are manifested in thebehavior and response of the eye, including the retina and the opticnerves. In addition, objective tests such as OKN, VEP and patternelectroretinograms (PERG) can be implemented in the systems and methodsof the invention. Objective tests are useful with infants andgeriatrics, as well as those who have difficulty communicating orfollowing specific directions.

Based on the image and/or data set information that is observed, theinvention provides an interpretive result. The term “interpretiveresult” is defined herein to mean a diagnosis (or a proposed diagnosis),or a change in physical condition or medical status over time, which amedical practitioner can consult in order to propose a course oftreatment for the individual patient in question. It is not to beinferred that the suggested diagnosis or indication of physicalcondition or medical status is to be taken as medical advice per se, butrather should be understood as an aid to a practitioner, who must stillapply his or her best medical judgment in counseling the patient.

Turning to FIG. 2, there is shown a schematic representation of anexemplary apparatus 100 suitable for use according to principles of theinvention. The apparatus 100 comprises a core portion 110 that in someembodiments can be portable or hand held. The core portion 110 comprisesa processor 112, which in some embodiments is a single board computer(SBC). The SBC is based on a microprocessor, such as an Intel x86 familymember or an equivalent processor. The processor 112 communicates with amicrocontroller (MCU) 114 by way of a bus 115, which is in oneembodiment an RS-232 bus. In some embodiments the MCU 114 is a MotorolaMC68332, which is a highly-integrated 32 bit microcontroller thatcombines high-performance data manipulation capabilities with peripheralsubsystems. The Motorola MC68332 comprises a 32 bit CPU, a systemintegration module, a time processing unit, a queued serial module and a2 Kbyte static RAM module with time processing unit emulationcapability. A memory device 116 is connected bi-directionally with theprocessor 112. The memory device can be any conventionalmachine-readable and -writeable storage device, including any or all ofRAM, DRAM, SDRAM, magnetic memory, and optical memory. The core portion110 also comprises a port 118, such as a universal serial bus (USB) orwireless port, for attaching external devices, such as a retina camera134, to the core portion 110. In some embodiments, an optional port 119is provided for attaching one or more electrodes 135, other signalacquisition hardware, to the core portion 110.

The core portion 110 also comprises an eye monitoring device 120 formonitoring an eye of a person being tested or evaluated, includingmotion of the eye. In FIG. 2, the eye monitoring device 120 isrepresented by a video camera; however, another embodiment is describedhereinbelow, in which a simpler and less expensive device comprising oneor more linear charge-coupled device (CCD) arrays is presented. The coreportion 110 further comprises a display 122, for displaying informationto an operator of the instrument, which display 122 in some embodimentsis a liquid crystal display (LCD). Additional portions of the instrumentare attached to the core portion 110.

In some embodiments, the core portion 110 is connected to one or more ofoperator input devices, which in some embodiments are a keyboard 124, amouse 126, or other devices such as a microphone (not shown). Theoperator input devices communicate with the processor 112 by way of anyconventional wired or wireless connection. In some embodiments, the coreportion 110 is connected to one or more output devices such as a printer128 or a speaker (not shown) for communicating to a user of for creatinga hard copy of a record, such as the observations and assessments thatare generated during a test. By use of the operator input and outputdevices, an operator can introduce, and can record as hard copy,information such as a person's name, other identifying information, andother patent-related information such as tonometer intraocular pressure,patient-history, family history, blood pressure, vital signs,medication, and pupillometry, as well as any test conditions, such as anapplied stress. An applied stress can comprise any one of intra ocularpressure variation, blood pressure variation, oxygen concentrationvariation, exercise, flashing light, drug administration, administrationof insulin, and administration of glucose, or combinations thereof.

A display 130 is provided for displaying test patterns or other materialto a person being tested. The display 130 is connected to the coreportion 110 by way of an electrical connector and cable 131 and receivessignals from the MCU 114 as input to be displayed. The core portion 110also has attached thereto a response device 132, such as a mouse or abutton that can be manipulated or otherwise activated by a person beingtested to communicate responses to the MCU 114 by way of a cable andconnector 133. In some embodiments, the display 130 and the responsedevice are a unitary device, such as a touchscreen, and/or theconnections with the MCU 114 are made by wireless methods, such as RF orinfrared communication links using any conventional wireless technology(for example, 802.11a, 802.11b, or 802.11g).

The core portion 110 is connected to a retina camera 134 by way of theport 118, for viewing the fundus of an eye. In one embodiment, theretina camera 134 is a device such as the Welch Allyn Model 11820PanOptic™ Opthalmoscope, available from Welch Allyn, Skaneateles Falls,N.Y., with the addition of a video pickup to provide an electrical inputsignal to the core portion 110 of the apparatus 100.

In one embodiment, the retinal camera comprises a sensor such as a CCDarray that converts detected light into charge signals. The chargesignals are in general proportional to an illumination level and aduration of an exposure. The charge signals are converted, on a pixel bypixel basis, into analog signals or digital signals, as may be desiredusing conventional circuitry, such as switching circuitry, sample andhold circuitry, amplification circuitry, filters, and analog to digitalconverters. Digital representations of the images detected can beprovided with resolution defined by the capability of an analog todigital converter, ranging today from one bit resolution to 24 bitresolution, and with higher resolution as may become possible in thefuture. Both gray scale and color can be resolved. Additional detaileddescription of embodiments of video devices suitable for use accordingto principles of the invention is presented in U.S. Pat. No. 6,527,390B2 and U.S. Patent Application Publication No. U.S. 2002/0097379 A1,both of which are assigned to the common assignee of this application,and the entire contents of each of which is hereby incorporated hereinby reference.

In some embodiments, one or more electrodes 135 can be attached to thecore portion 110 by way of a port 119. The one or more electrodes 135,or other signal acquisition hardware, are used to acquire electricalsignals, for example, electrical potentials generated during testing,such as visually evoked potentials or other electrical signals useful indetecting responses of a person being tested.

A computer 136, which in various embodiments is a personal computer, alaptop computer, or another general purpose programmable computer ofsimilar or greater capability, is provided for analysis of images anddata sets that are collected in the course of testing a person. Theimages and data sets are communicated from the core portion 110 to thecomputer 136 by way of any of a wired connection link 140, such as anRS-232 communication bus, a wireless communication link 142, such as RFor infrared, or by transfer using removable media such as a CD-RW disc138 or a floppy or zip disk 144. In some embodiments, communication fromthe computer 136 to the core portion 110 is provided by any of the wiredlink 140, wireless link 142, and transfer using removable media such asCD-RW disc 138 and floppy or zip disk 144, so that commands in the formof programs, program modules, or individual commands to perform aspecific action can be downloaded from the computer 136 to the coreportion 110, or can be accessed by the core portion 110 while residentat the computer 136. To this end, each of the computer 136 and the coreportion 110 are provided with the appropriate ports and/or read-writedevices for reading and writing media as necessary. The core portion 110and the computer 136, as well as the other attached devices, are poweredby conventional line voltage connections using wall plugs and powersupplies, or by the use of batteries, as appropriate, depending on theintended use of the apparatus, e.g., in an office setting, or in a fieldsetting.

FIGS. 3A-3D show generally an approach to providing an eye monitoringdevice 120 useful for monitoring the motion of an eye. FIG. 3A shows aschematic diagram 200 of the disposition of an eye monitoring device 120relative to an eye 260 of a person being tested. In addition, FIG. 3Aindicates at a high level the relative disposition of components withinthe eye monitoring device 120, which is a hand held, portable device inthe embodiment depicted. The eye monitoring device 120 comprises, in oneembodiment, a handle 210 that provides a griping structure for apractitioner to hold and position the eye monitoring device 120 relativeto the eye 260. The handle 210 is adapted to contain the battery usefulfor operating the device and the electronics useful for manipulatingdata, providing control signals, and communicating commands and data toand from the eye monitoring device 120. A head portion 220 of the eyemonitoring device 120 contains a display 230, such as a CRT, fordisplaying a test pattern to the eye 260. The head portion 220additionally contains one or more sensors 240 that are aimed to detectlight reflected from a surface of the eye 260. The one or more sensors240 in one embodiment are 1024.times.1 CCD arrays capable of detectinglight at each of 1024 pixel locations, and providing an electricalsignal proportional to an intensity of light detected at each pixel. Theone or more sensors 240 are focused on a surface of the eye 260 byoptics 250, which can be constructed of one or more components made fromany convenient optically transmissive material such as glass or plastic.

FIG. 3B shows a diagram 202 that depicts the interrelationship among thefeatures of an eye 260 of a person being tested, and the areas 242, 244of the eye sensed by two sensors. The eye 260 is being viewed straighton in FIG. 3B, and features of the eye 260 including the white area 262,the iris 264, and the limbus 266 of the iris 264 are represented. Twoareas of focus 242, 244 of two sensors, such as the one or more sensor240 of FIG. 3A, are depicted on the surface of the eye 260. One area offocus 242 is positioned along an imaginary horizontal line (i.e., line268 in FIG. 3C) passing through the center of substantially circularlimbus 266. A second area of focus 244 is positioned along a secondimaginary horizontal line parallel to the first imaginary horizontalline, but above (or alternatively, below) the first area of focus 242 byan offset of dimensions of millimeters. Each of the two sensors (notshown) can detect an intensity of light reflected from differentlocations on the surface of the eye 260. A white portion 262 of thesurface of the eye 260 will in general reflect light more strongly thana darker portion of the surface of the eye 260, such as the iris 264, orthe pupil of the eye situated within the iris 264. As the eye moves, thechange in intensity of light reflected from the white portion 262 ascompared to the intensity of light reflected from the iris 264 istracked. Position is measured as a pixel location counted from one endof a sensor 240. The position of the change in intensity of reflectedlight corresponds to the location of the limbus 266. When the twosensors detect a change in the position of the limbus, the direction ofmotion of the eye can be deduced. By applying standard discrete timeanalysis, the velocity of the motion can also be deduced as x-axisvelocity=k(DX/DT), where k is a constant, DX is a change in positionalong an X axis, and DT is a change in time, and a y-axis velocity canbe determined as y axis velocity=k(DY/DT), where DY is a change inposition along a Y axis. As is well known in the mathematical analysisarts, two data inputs that are independent with respect to x- and y-axismotion are sufficient to determine both motions and their velocities.

FIG. 3C shows a diagram 204 that depicts the interrelationship betweenthe features of an eye 260 of a person being tested, and the area 242 ofthe eye sensed by one sensor. In FIG. 3C, the features corresponding tothose described with respect to FIG. 3B are indicated by like numerals.In the event that the eye 260 only moves horizontally, the x-axis motionis the only motion that is detected. Accordingly, only one data inputthat tracks x-axis motion is required, and the area 242 aligned alongthe centerline 268 of the limbus 266 is sufficient. A procedure usefulin constraining the motion of the eye 260 to the horizontal direction isdescribed next.

FIG. 3D shows a diagram 206 that depicts a test pattern 282 and afixation signal 290 that is useful for fixating an eye 260 of a personbeing tested when one sensor is employed in the eye monitoring device120. The CRT 230 of FIG. 3A provides a frame 280 of visually displayedinformation. A test pattern 282 is disposed within frame 280, comprisingone or more vertical lines 284 that can be traversed horizontally over abackground 286. The eye 260 of the person being tested will in generalattempt to follow the motion of the one or more lines 284. However,there in general can be a wandering of the gaze of the eye 260 in anupward or downward direction while the eye 260 attempts to follow thehorizontal motion of the lines 284. The fixation signal 290, which is aprominent solid line segment disposed horizontally across the testpattern 282, within a field of view of substantially 5 degrees totalangular height or less, is provided to prompt the eye 260 to fixatevertically along the horizontal line 290 while not interfering with theproclivity of the eye 260 to follow the horizontal motion of the one ormore vertical lines 284.

FIG. 4 is a flow chart 400 showing the steps in the operation of theinstrument and method of the invention, or alternatively, showing theinterrelationships among the modules comprising apparatus according tothe invention. The description will be presented in terms of modules,but those of ordinary skill will also understand the figure asdescribing the steps of performing the method of the invention.Information is collected by imager 410 and data set collector 420 asnecessary. In one embodiment, the information is a plurality of images.In another embodiment, the information is a plurality of data sets. Inyet another embodiment, the information comprises at least one image andat least one data set. The information is transferred to the dataanalysis module 430 for analysis. A memory module 470 in bi-directionalcommunication with the data analysis module 430 can record informationsent from the data analysis module 430 in raw form, in analyzed form, orin both forms. Furthermore, the memory module 470 can store information,including as an archival storage, and can provide stored information tothe data analysis module 430 as required. For example, the memory module470 can provide information that was recorded during a previous visit ofa patient to a medical practitioner for the purpose of comparing currentinformation observed from the patient with historical information.Archived information can be stored locally or at a remote location. Aremote storage capability, which is not shown, can be connected tomemory module 470 and or to data analysis module 430 by any convenientmeans, including wire connection, wireless connection, and by thephysical movement of storage media, such as floppy disks, CD-ROM disks,DVD disks, magnetic tape, memory cards, and similar moveable storagemedia.

A superposition module 440 is in bi-direction communication with thedata analysis module 430. Information can be sent from the data analysismodule 430 to the superposition module 440, and data that has beensubjected to superposition can be sent from the superposition module 440to the data analysis module 430. As described below with respect to FIG.5, the superposition module 440 in some embodiments comprises aplurality of other modules.

The data analysis module 430 is in communication with a data outputmodule 450, which can provide information to a user. The data analysismodule 430 is optionally in communication with a report module 460,which can provide reports to a user. The data analysis module 430 isoptionally in communication with a display module 480 that can displayimages, sets of data, and superpositions of information to a user forvisual examination of the information.

FIG. 5 is a diagram 500 depicting components of a superposition module440 according to the invention. The superposition module 440 canoptionally comprise first and second identification modules 510, 520that identify first and second fiduciary points in an image or a dataset. In some embodiments, the first and second identification modules510, 520 are the same module. The superposition module 440 alsooptionally comprises an orientation module 530, a scaling module 540,and a correspondence module 550. The orientation module 530 orientsimages or data sets to be superimposed about a fiduciary point so that afirst metric and a second metric are oriented in selected orientations.The scaling module 540 scales an image or data set so that a first unitof measure associated with the first metric and a second unit of measureassociated with the second metric in each image or data set to besuperimposed are substantially equal to selected first and secondvalues. The correspondence module 550 creates a one-to-onecorrespondence between the fiduciary point, the first metric and thesecond metric in a first image or data set to be superimposed with thefiduciary point, the first metric and the second metric in a secondimage or data set to be superimposed.

In some embodiments, the first metric and the second metric are firstand second axial directions. In one embodiment, the first and secondaxial directions are coplanar but not parallel axial directions, such astwo axes, for example the x and y axes in a Cartesian coordinate system.Other coordinate systems can be used equally well. In such anembodiment, the first unit of measure associated with the first metricis a length along the first axial direction, such as a number of unitsalong an x-direction, and the second unit of measure associated with thesecond metric is a length along the second axial direction, such as anumber of units along a y-direction. In other embodiments, the firstmetric is a first axial direction, the second metric is an angulardisplacement from the first axial direction, the first unit of measureassociated with the first metric is a length along the first axialdirection, and the second unit of measure associated with the secondmetric is a unit of angular measure. For example, the first metric is aheading or compass direction that is considered to be zero degreesrelative to an origin (i.e., due North on a map), and the first unit ofmeasure is a geometric distance along the heading (i.e., a radius of acircular arc), the second metric is an angle (i.e., θ degrees clockwiserotation), and the second unit of measure is an angular value, such asθ=90 degrees. When a plurality of images, a plurality of data sets, orat least one image and at least one data set are scaled, rotated and/ortranslated such that corresponding first and second metrics are made tocoincide, the plurality of images, the plurality of data sets, or the atleast one image and at least one data set will be capable of beingsuperimposed.

In the display of such images, one can present the images side by side,or in superimposed configuration, one upon the other. The images can becompared by simple superposition, to show interrelationship of one ormore features that appear in each. Alternatively, by superimposing oneimage on the “negative” of another, it is possible to make thedifference (or the change between a first image and a second image)readily apparent. For example, a new feature appearing in a later imagewill become the only feature (or a highlighted image) displayed in adisplay comprising a “negative” of a first image superimposed upon (orsummed with) a second, later, image. Images can be displayed in falsecolor as well, so that regions of data sets that comprise substantiallysimilar values can be readily discerned. For example, an image in whicha first color is used to represent data points below a threshold valueand a second color is used to represent data points exceeding thethreshold value provides a display for a viewer in which the regionshaving specified ranges of values are readily identified. As required,more than two ranges can be assigned, and corresponding different colorscan be used in the display of the data set.

FIG. 6 is a diagram 600 showing a region of frequency space having bothtemporal and spatial frequency variations, and indicating a typicalperson's reaction thereto, as is known in the prior art. FIG. 6 is basedon observations made by D. H. Kelly, which results were reported someyears ago. In FIG. 6, the horizontal axis 610 is a logarithmic axis thatrepresents the temporal frequency in cycles per second (cps) rangingfrom close to zero to approximately 100 cps. In FIG. 6, the verticalaxis 620 is a logarithmic axis that represents the spatial frequency incycles per degree (cpd) ranging from close to zero to approximately 20cpd. In this circumstance, degrees are measured as angular measure onthe retina of an eye. As can be seen, there is a region 630 extendingfrom about 7 cps to about 60 cps and from about 0.1 cpd to about 2 cpd,which region 630 is labeled “Spatial Frequency Doubling.” The region 630further includes a point indicated by the cross 635 that is in someembodiments a target spatial and temporal frequency operating point inthe vicinity of 25 cps and 0.3 cpd. Within the Spatial FrequencyDoubling region 630, a person with normal vision see a pattern thatappears to be doubled in spatial frequency from its actual spatialfrequency. Persons with compromised vision, or with other neurologicaldifficulties, have difficulty perceiving the doubled spatial frequencypattern, or see it only at higher contrast.

FIGS. 7A and 7B are drawings that depict a display space 710 that issegmented and includes an illustrative contrast pattern 720. In FIGS. 7Aand 7B, one segment 715 includes a high contrast pattern 720 and onesegment 715 includes a lower contrast pattern 720′, respectively. Eachof FIGS. 7A and 7B include a central region 730 that can in someembodiments be used to locate a fixation element, or a differentcontrast pattern than the patterns shown in segment 715. As may beunderstood from comparison of FIGS. 7A and 7B, the more stronglycontrasting pattern 720 of FIG. 7A can be transformed into the lowcontrast pattern of FIG. 7B by decreasing the dynamic excursion (ordynamic range) of the signal comprising high contrast pattern 720. Highcontrast pattern 720 is generated by providing a sinusoidally varyingsignal having bright and dim extremes, or strongly illuminated regionsand weakly illuminated regions. It is expected that those withcompromised neurological condition will perceive the contrast signal todisappear at a higher contrast level threshold than those with normalvision and normal neurological conditions. Dyslexia may be indicated byan inappropriate response to contrast sensitivity tests, because indyslexia the eye and the brain collaboratively misinterpret the spatialrelationships in data.

FIGS. 8A, 8B and 8C are diagrams that show the relationship between animage and a data set, two images taken at different times, and a seriesof images, false color data representations, and data sets,respectively. As depicted in FIGS. 8A, 8B and 8C, the interrelatedimages and data sets are displayed side-by-side. It will be understood,perhaps most readily by considering the two images of FIG. 8B, that twoor more pieces of information can also be superimposed. Carefulcomparison of the leftmost image of FIG. 8A with either of the images ofFIG. 8B will show that the leftmost image of FIG. 8A is larger in sizethan either image of FIG. 8B. As is seen in the images of FIG. 8B, manyfeatures of one image are also present in the other image, and the twoimages could easily be presented as either the superposition of one onthe other, or the superposition of one over the negative image of theother, thereby highlighting the differences between the two images. Inone embodiment, viewing the information in side-by-side presentationmakes it easier to compare information, and may allow certain forms ofanalysis, but requires the viewer to synthesize the data to find certaincorrespondences. In other embodiments that use superposition, benefitsthat accrue include the ability to highlight, the ability to subtract orotherwise process information, and the ability to assure that two piecesof information are representative of the same area or feature.

In FIG. 8A, the left image is an image 805 of a retina of an eye,including a macula 810 near the center of the image. In FIG. 8A, theright image 808 is a map of a contrast level observation, in which thecentral region 730 corresponds to the macula 810, and the region 715having the contrast pattern 720 therein is intended to convey theinformation that the observed response of the eye was acceptable in thatregion 715.

In FIG. 8B, the left image 805′ is a first image of a retina of an eye,in which the macula 810 is again visible. The right image is an imagethat represents a second image of the same retina taken 6 months later,in which the macula 810 is again visible. However, in the later rightimage 805″, a new feature 820 appears to the left of the macula 810. Theside-by-side presentation in FIG. 8B is intended to show that for highlysimilar images, it is relatively easy to compare two or more images, ascan be seen in a comparison of the two images in FIG. 8B, wherein alarge number of features can be observed to be substantially common toboth images, such as the position and shape of imaged blood vessels 830.While the new feature 820 is readily apparent, it is not clear from theimage whether the new feature 820 represents an active proliferation ofcapillaries (i.e., blood is still circulating in blood vessels) orwhether the new feature is a blood clot that has long since ceased tocirculate. More information is available from a consideration of theimages shown in FIG. 8C.

FIG. 8C comprises four pieces of information. The leftmost image is theimage 805″ as seen in FIG. 8B, right side. This is a high resolutionimage that is displayed on a pixel by pixel basis, wherein much detailis available for analysis. Again, the feature 820 is visible. The nextpanel in FIG. 8C (i.e., the second image from the left) is a false coloroxygen saturation view 820A of the region of the retina in the vicinityof the new feature 820. In the second image 820A, one can discern thatthe new feature 820 is a region centered on a junction 825 of bloodvessels 830, which gives further credence to the analysis that thefeature 820 represents blood high in oxygen. The next image 806 (i.e.,the third image from the left) is a false color thermal image taken atlower resolution that the second image from the left (i.e., 4 by 4pixels rather than one-by one pixel), which image shows the new feature820, for example, as a red (false color) square region 820′ at thejunction 825 of a yellow (false color) blood vessels 830. The red falsecolor is representative of a higher temperature than the immediatesurroundings, suggesting that the new feature 820 is a proliferation ofcapillaries that comprises fresh, warm blood, rather than an old bleedwhich would have reached the same background temperature as thesurrounding tissue, and therefore would have been represented by thesame color (green). A second red false color region 832 is also shown inthe false color image, the second red false color region correspondingto the macula 830, which is rich in blood vessels, and therefore wouldbe expected to be somewhat warmer than the surrounding area. Therightmost panel of FIG. 8C is a representation 809 of a data setobtained from a contrast sensitivity measurement, in which the centralregion 812 corresponds to the macula 810 of the leftmost image 805″. Thedata set is represented at a rather low resolution as compared to theleftmost image 805″, for example using a 10 pixel by 10 pixelresolution. The gray region 850 of the contrast sensitivity data setrepresents a region of severely degraded response, which corresponds tothe location of the new feature 820 in the leftmost panel of FIG. 8C.One can then recognize from the aggregation or interrelation of images805″, 820A, 806, and 809, that the new feature 820 gives all theindications of a region representing an active capillary structure, thestructure negatively impacting the vision of the eye underconsideration.

FIG. 9 is an illustrative schematic in exploded form showing therelationship among superimposed images and/or data sets. In FIG. 9 thereare three parallel planes 910, 920 and 930. Situated on each plane is animage or a map of a data set. For example, there appears on plane 910image 912 that is a photographic image of the fundus of an eye such asis captured by a retinal camera 134. Along axis A, which is denoted by adotted line extending between the planes 910, 920, 930, there is inimage 912 a spot 914, which corresponds to the area of capillariesdescribed as the new feature 820 of FIGS. 8B-8C. Along axis B, which isalso denoted by a dotted line extending between the planes 910, 920,930, there is in image 912 a macula 916, which corresponds to the maculaof FIGS. 8A-8C. There are blood vessels 913 that have a junction 915, aswell as other features visible in image 912.

In plane 920 of FIG. 9 there appears an image that is a false colorthermal image taken at a lower resolution than the second image from theleft (e.g., 4 by 4 pixels rather than one-by one pixel), which imageshows the new feature 820 as a red (false color) rectangular region 924at the junction 925 of yellow (false color) blood vessels 923. The Aaxis passes through the rectangular region 924 representing the falsecolor image of the new feature 820. The B axis passes through the squarefalse color region 926 corresponding to the macula 916 of the eye.

In plane 930 of FIG. 9 there appears a map 932 corresponding to a dataset recorded as a result of a contrast sensitivity test. In the map 932there is a fixation pattern 936 which is the area upon which the gaze ofthe eye under test is expected to fall, and as described above, is alocation where the gaze of the eye can be observed to fall byinstrumentation of the invention. Accordingly, the fixation pattern 936,or a selected pixel of the fixation pattern 936, such as the center ofthe fixation pattern 936, can be placed along Axis B so as to coincidewith (or to be superimposed upon) the image of the macula 916 and thefalse color image 926 of the macula. Also, the region 934 of the map 932corresponding to the data set obtained in the contrast sensitivity testindicates a diminution in the ability of the eye to perceive thecontrast pattern, which diminution is denoted by a gray hue in area 934.In some embodiments, the depth or intensity of the gray hue, or the useof a range of false colors, can be used to represent the severity of thediminution of perception. The region 934 is aligned with Axis A,corresponding to the area of the retina having the new feature 820 thatis depicted as region 914 of the fundus photograph 912. As needed, thesizes of one or more of the various images and maps or otherrepresentations of data sets can be expanded or contracted so thatsuperposition is possible. Furthermore, any of the images orrepresentations of data sets can be translated and/or rotated to orientone with respect to another so that superposition can be accomplished.As is understood in the geometric arts, superposition can be attained bysuperimposing two selected points in a first image with thecorresponding two selected points in a second image. Superposition canalso be attained by defining a pair of coplanar but not parallel vectorsin each image, causing the dimensions of the images to be commensurateby expanding or contracting at least one image as needed, and aligningthe vectors. Superposition can also be accomplished by defining anorigin and a vector in each image, causing the dimensions of the imagesto be commensurate by expanding or contracting at least one image asneeded, and aligning the origins and the vectors.

According to principles of the invention, it is possible to determineblood glucose by measuring the eye of a patient using an instrument asshown in FIG. 10, and described in more detail below.

The operation of the instrument is based on the observation that inhumans, and perhaps in other animals, the retina of the eye has one ofthe fastest metabolic rates in the body. Diabetes is a disease that ischaracterized by poor control of blood glucose. Diabetics attempt tocontrol their blood glucose levels by balancing food intake, exerciseand medication, such as insulin or other medications. In order todetermine whether and how much insulin to administer, the blood glucoselevel of the individual must be measured. Today, diabetics can berequired to draw blood, commonly by pricking a finger, several times aday. The procedure of drawing blood can be painful and invasive, andcompliance with a strict medical regimen may be affected in a negativeway.

The blood glucose determination apparatus of the invention, and itsmethod of use, may have applicability in blood glucose monitoring indiabetics, with several advantages. First, the measurement does notrequire the drawing of blood, and is therefore painless. In addition,the measurement device will not require the use of consumables, such aschemicals or treated strips that interact with drawn bodily fluids. Thelack of consumables, other than a replaceable battery, will reduce theoperating cost per test, making testing possible at lower operatingcosts than in conventional tests that require interaction of a bodilyfluid with a test medium. In addition, the absence of consumables willmake testing more convenient in that the user does not need to rememberto transport consumable items when he or she travels from home, evenduring the day. Another benefit is the fact that the test will berelatively unobtrusive and not embarrassing, so that it can be performedquickly and in public settings as may be required.

Experimenters have studied the effects of glucose on the retina, theheart, and the kidneys for many years. These organs are well-known to benegatively affected in persons suffering from diabetes. One relationthat has been noted is the ability of the retina to observe or determinecontrast, which varies with the blood glucose level. In particular, arelation between a person's visual contrast sensitivity and the person'sblood glucose level may provide a basis for measuring the blood glucoselevel. It may be necessary or advantageous to calibrate the measurementby the use of a blood glucose measurement using drawn blood. However,once the calibration is performed, the necessity to draw blood to makeactual measurements is obviated. The calibration might also be performedby using different blood glucose levels, e.g., high blood glucose,normal blood glucose, and low blood glucose, which levels may be inducedby deliberate administration of foodstuffs or by the deliberatewithholding of food and having the person to be tested perform exercise.

The apparatus 1000 of FIG. 10 is in one embodiment a hand-held devicethat measures a person's visual contrast sensitivity in the same waythat the FDT device measures contrast sensitivity in persons exhibitingglaucoma and/or other neurological disorders. As shown in FIG. 10, theapparatus 1000 comprises a power supply 1010 such as a battery andelectronics 1020 for generating and displaying a contrast pattern 1030that appears on a display 1040 and for computing a result of a bloodglucose measurement. In one embodiment, the electronics 1020 comprises amicroprocessor or microcontroller and memory, as well as the necessarysignal acquisition and conditioning hardware for responding to commandsfrom the user, as well as software that may be recorded in nonvolatileform in a machine-readable medium. In one embodiment, the display 1040will be an LCD similar to those used in present-day camcorders. In otherembodiments, other display technology may be used. The apparatus 1000also comprises a lens 1050 for focusing an image of the contrast pattern1030 so that the image may be viewed by an eye 1070 of a user. Thecontrast pattern 1030 can also include a fixation element 1032, forassisting the user in fixing his or her gaze on a particular location ofthe display. The apparatus 1000 also can comprise an optical element1060 useful for changing a size of the image and/or for causing thelight from the image to be correctly oriented for the user to view theimage. In some embodiments, the optical element 1060 is a mirror, whichcan be a planar mirror, a convex mirror, or a concave mirror asrequired. The eye 1070 as shown comprises an iris 1072 and a lens 1074,as is commonly found in eyes for causing an image to fall on a retina1076 of the eye.

In use, the user holds the apparatus 1000 in a position such that theuser can observe the contrast pattern 1030 and the fixation element1032. The fixation element 1032 help to insure that the contrast pattern1030 will fall on the same portion of the user's eye 1070, such that thesame area of the retina 1076 of the eye 1070 is interrogated. The areacan be any area of the retina that represents the test subject'sreaction to blood glucose level or concentration. In some embodiments,the area is the macula of the eye 1070, in which case the contrastpattern 1030 and the fixation element 1032 are coincident. For example,the contrast pattern 1030 can be centered on the fixation element 1032.In one embodiment, the user can activate a button 1080 on the apparatus1000 during a time when he or she can see the contrast pattern 1030. Thebutton 1080 is connected electrically to the electronics 1020. In oneembodiment, the user releases the button 1080 to indicate that the usercan no longer distinguish the contrast sensitivity pattern 1030, therebycompleting a test cycle. The contrast sensitivity pattern 1030 firstappears with dark lines and light lines, which respectively becomelighter and darker with time. At some point, either when the two sets oflines in the contrast sensitivity pattern 1030 have the same opticalcharacteristic and cease to be distinguishable, or when the user is nolonger able to distinguish between the light and dark sets of lines, theuser would be expected to release the button 1080. After the electronics1020 processes the data it receives, and computes a blood glucose levelfor the user, the result may in some embodiments be displayed to theuser by being presented on the display 1040 of the apparatus 1000 in anyof an alphanumeric format, a pictorial format (i.e., a graphic or anicon), an audible signal provided by a speaker 1082, a tactile signalprovided by a vibrator, or any combination of signals. In alternativeembodiments, the result can be transferred, for example by wirelesscommunication, to another device, such as a personal digital assistant,a cellular telephone, a computer, a data recorder, a printer, or anexternal display. For example, a person may wish to have a result thatindicates a serious abnormality, such as severe hypoglycemia, reportedto another trusted party to make sure that appropriate medicalintervention takes place.

In a further embodiment, the apparatus described hereinabove inparagraphs [0075] to [0119] additionally comprises an analysis modulecomprising a programmable processor and computer software recorded on acomputer-readable medium. The computer software (or alternatively“software”), when operating, performs a plurality of steps. The softwarecontrols the operation of the apparatus generally, including controllinginput and output functions of the apparatus, such as receiving commandsand data from a user of the apparatus to cause the apparatus to performits operations, and providing to the user of the apparatus information,such as information relating to the outcome of one or more analyses,information describing the condition of the apparatus, prompts or otherinformation that indicates that the user may provide additionalinformation about the person being tested so as to improve the outcomeof the analysis performed by the apparatus. As regards the detailedoperation of the software, in one embodiment the software interrelatesat least two disparate kinds of information selected from one or moreimages and one or more data sets to attempt to obtain an interpretiveresult relating to the condition of the person. In the event that theattempt to obtain an interpretive result relating to the condition ofthe person provides a result representing a state of normal health, thesoftware controls the recording the result and terminating the analysis.

In the event that the attempt to obtain an interpretive result relatingto the condition of the person provides a result representing a state ofhealth that is not normal health, the software operates to attempt todistinguish a condition represented by the state of health that is notnormal health. In the event that the attempt to distinguish thecondition represented by the state of health that is not normal healthis successful, the software operates to report an interpretive result ofthe condition, operates to record information for later use, andterminates the analysis.

In the event that the attempt to distinguish the condition representedby the state of health that is not normal health is unsuccessful, thesoftware can additionally report the failure to distinguish a condition.Optionally, the software can additionally prompt a user of the apparatusto provide additional information about the person. Optionally, thesoftware can prompt a user of the apparatus that additional testing canbe performed.

The software can additionally operate to iteratively repeat theinterrelating step and, as appropriate, each of the conditional stepsusing the additional information provided in response to the prompt inaddition to the at least two disparate kinds of information selectedfrom one or more images and one or more data sets to attempt to obtainan interpretive result relating to the condition of the person. Anyspecific step can be omitted in an iteration cycle if it appears thatthe step is unnecessary. The iteration can continue until any of thefollowing conditions occurs, and in general, will terminate when thefirst of the following conditions does occur: after reporting aninterpretive result; operating until an iteratively repeating step isperformed a predetermined number of times without distinguishing acondition represented by a state of health that is not normal health;operating until an iteratively repeating step is performed until aspecified period of time elapses without distinguishing a conditionrepresented by a state of health that is not normal health; andoperating until a user of the apparatus determines that the analysisshould be terminated, and intervenes to terminate the analysis.

The disease referred to as ALS is also known as amyotrophic lateralsclerosis (or Lou Gehrig's disease).

FIG. 11 is a flow chart 1100 showing the steps in a measurement process.The process described by the flow chart begins with initialization ofthe computer system and the software operating on it, including theusual internal checks for proper operation, and initialization of allparameters to default values that the instrument requires for operation,which parameter values in some embodiments are retrieved from a memoryaccessible by the computer. In some embodiments, a user of theinstrument can change the default values in order to perform tests andanalysis.

The box 1105 labeled “Start” is intended to represent all of theconventional start-up and “housekeeping” processes that take place whena computerized system is initialized, and can include such events asretrieval of information from a computer accessible memory, a userentering information that identifies the user as a person authorized tooperate the system, entry by a user of information that identifies theperson who is to be tested, entry of values to replace default values,entry of the time and date (which in some embodiments may beautomatically entered), entry of information about the person beingtested (for example, vital signs information and/or some or all of apatient history), and entry or retrieval from a memory of otherinformation such as billing or insurance information.

When the computer software is operating on the programmable computer, itcan cause the following steps to be performed. In some embodiments, thecomputer and software are used in obtaining one or both of images (forexample, images of an eye or parts thereof) and data sets (for example,data relating to the response of the person to various stimuli). As partof a test, indicated at box 1110, the software can interrelate at leasttwo disparate kinds of information selected from one or more images andone or more data sets to attempt to obtain an interpretive resultrelating to the condition of the person. The computer and softwareanalyze the interrelated information (images, data and otherinformation).

As indicated at diamond 1115, the analysis attempts to determine whetherthe images, data and other information are consistent with a normalstate of health or are consistent with a state of health that differsfrom a normal state of health, and to obtain an interpretive resultbased on the analysis. In the event that the attempt to obtain aninterpretive result relating to the condition of the person provides aresult representing a state of normal health, corresponding to the arrowlabeled “YES” leaving diamond 1115, the software causes the interpretiveresult to be recorded, and optionally reported, and the test isterminated, as indicated by box 1120.

In the event that the attempt to obtain an interpretive result relatingto the condition of the person provides a result representing a state ofhealth that is not normal health, the process follows the arrow labeled“NO” leaving diamond 1115, and the process continues as indicated at box1125, representing an attempt by the operating software to distinguish acondition represented by the state of health that is not normal health.

At diamond 1130, the software determines whether there has occurred asuccessful analysis that distinguishes a particular state of health thatis not normal health (e.g., a specific disease condition is indicated bythe information). In the event that the attempt to distinguish thecondition represented by the state of health that is not normal healthis successful, the process proceeds according to the arrow labeled “YESleaving diamond 1130, and the software provides an interpretive resultof the condition. If the software indicates that the confidence level ofthe analysis is high enough, the analysis can be terminated, asindicated at box 1120.

However, if the software either does not identify a specific conditionthat is consistent with the information that has been analyzed, or ifthe confidence level associated with the analysis is less than somepredetermined value, for example 75% confidence that the conditionidentified is correct, the process can continue according to the arrowlabeled “NO” leaving diamond 1130. As will be understood, the user canbe signaled that the outcome of the analysis is either indeterminate orof low confidence by either of two possible methods. One method issimply to fail to provide an interpretive result. The second method isto report the failure to distinguish a condition.

The software can cause the apparatus optionally to prompt a user of theapparatus that additional tests can be performed, as indicated at box1145. The software can cause the apparatus optionally to prompt a userof the apparatus to provide additional information about the person, asindicated at box 1150. Using the additional information, and/or theresults of additional tests that generate additional images and/or datasets, the software can again perform analysis as indicated at box 1110,and subsequent steps as indicated above.

As indicated by the box 1140 shown in broken outline and labeledITERATE, the software can cause the iterative repetition of the analysisto provide an interpretive result. The iterative repetition can continueuntil the first to occur of: the analysis is terminated according tostep 1120; the iteratively repeating step is performed a predeterminednumber of times without distinguishing the condition represented by thestate of health that is not normal health; the iteratively repeatingstep is performed until a specified period of time elapses withoutdistinguishing the condition represented by the state of health that isnot normal health; and a user of the apparatus determines that theanalysis should be terminated, and intervenes to terminate the analysis.

Additional tests 1145 and addition information 1150 about a personcomprises any one or more of: collecting an additional image; collectionof an additional data set; additional information from a magneticresonance imaging (MRI) test, which can be a structural MRI test or afunctional MRI test; patient history data, vital signs data, additionalinformation from a positron emission tomography (PET) test which can bean FDG-PET glucose determination or a C-PK11195-PET test, additionalinformation from a brain biopsy, and additional information from acognitive impairment test. The order of performing the steps ofobtaining an image, obtaining a data set indicative of a neurologicaldisorder, and obtaining said additional information about said person isnot critical, and may be performed in any order that is convenient.

Sequential testing can be performed on a person to identify a diseasecondition that may exist. The person is tested first with the overallscreening test to establish if he or she is normal or abnormal (e.g.,having one or more diseases, but the exact identity of the disease thatmay be present is not known prior to testing). If the person is normalaccording to the screening test, the data observed can be recorded foruse as a baseline at a later time, and the testing terminates. However,if it appears that an abnormality (which is taken to be indicative of adisease condition) exists, the person would be tested a second time witha different test more specific to one of the diseases that theinstrument embodying the invention can distinguish. In the furthertesting, the apparatus uses a modified test, which can include one ormore changes in spatial frequency, temporal frequency, magnitude or sizeof stimuli, location of stimuli, color, and contrast. The furthertesting test has each of those parameters optimized so as to attempt toidentify the presence of one of the diseases and not the others. If theperson appears to be normal based on the second test, then a third testcan be performed with a different set of parameters. Additionalinformation can also be used in performing an analysis of the results ofa test, so as to provide an interpretive result. It is possible toiteratively repeat the testing until there is an identification of oneor more diseases the person appears to have (since it is possible tohave both glaucoma and AD as an example).

In some embodiments, the apparatus for obtaining an interpretive resultrelating to a condition of a person is used in commercial activity, andfinancial compensation is received for performing a selected one ofdisplaying the interpretive result and reporting the interpretiveresult. In some instances, financial compensation is received forperforming the testing.

In some embodiments, the apparatus for obtaining an interpretive resultrelating to a condition of a person is used is a manner wherein theinterpretive result comprises an indication of a tendency to develop adisease condition.

In some embodiments, the apparatus for obtaining an interpretive resultrelating to a condition of a person comprises software recorded on amachine readable medium. In some embodiments, the software whenoperating repeats its operation for data relating to a second eye of theperson to determine a condition of health of the person. In someembodiments, the condition of health of the person obtained from datafrom one of the first eye of the person and the second eye of the personis used as a baseline condition for testing of the other of the firsteye of the person and the second eye of the person. In some embodiments,the condition of health of the person is obtained from data relating toboth the first eye of the person and the second eye of the person.

As used in the present application, the term “venue” in any of itsvariant forms is intended to be interpreted broadly and to include, forexample, medical office settings, field test settings (e.g., testing aspart of an emergency response at a field location), other settings suchas the lobby of a building where screening of individuals for variousmedical conditions, such as high blood pressure, are from time to timeperformed, settings such as mobile testing facilities (e.g., medicaltrailers used for screening persons in a selected geographical area),and commercial testing facilities, such as imaging centers of the typethat perform medical imaging.

Optical neuroma is one or more cancers that affect an optic nerve.

Stroke is a form of head trauma. A second form of head trauma is a blowto, or severe shaking of, the head. It can in some instances belocalized on one side of the brain or in a specific region of the brain.Stroke can involve either or both of a loss of blood circulation in atleast a portion of the brain that can result in death of tissue (forexample, caused by a blockage in a blood vessel, such as a blood clotthat occludes the vessel) or a leakage of blood from a blood vessel thatcan cause problems both from lack of oxygen in portions of the brainthat loose circulation and from added fluid volume and pressure in thevicinity of the leakage (for example, resulting from a rupture in ablood vessel caused by elevated blood pressure or by loss of elasticityof the blood vessel, or both).

Tests and their analysis can provide information about the site and thecause of loss of neurological function, such as which side or wherewithin the brain a loss occurs, whether the loss is localized in an eye(such as damage to a retina or cells within the eye), or whether a lossoccurs in the nerves between the eye and the brain, or whether a lossoccurs in the brain.

With regard to the outcome of an analysis, it is expected that there canoccur situations in which the result of the analysis is consistent witha first possible state of health that is not normal health with a firstprobability, and the result of the analysis is also consistent with asecond possible state of health that is not normal health with a secondprobability. If the difference between the first probability and thesecond probability is not sufficient large to make a cleardifferentiation between the first and second states of health that arenot normal health, the apparatus can provide a report indicating thatthe first condition is likely to the extent of a first percentage, andthe second condition is likely to the extent of a second percentage. Theapparatus can optionally prompt the user of the apparatus to provideadditional information about the person being tested. In someembodiments, the apparatus can iteratively repeat analyses using theadditional information to refine the likelihood that the firstcondition, the second condition, or other conditions different from astate of normal health are consistent with the images, data and otherinformation that may have been utilized in the analysis. The apparatuscan report the results of its analysis, as an interpretive result, andnot as a medical diagnosis, to a user thereof. The operation of theapparatus can terminate under any of several conditions, such as afterreporting an interpretive result; operating until an iterativelyrepeating step is performed a predetermined number of times withoutdistinguishing a condition represented by a state of health that is notnormal health; operating until an iteratively repeating step isperformed until a specified period of time elapses withoutdistinguishing a condition represented by a state of health that is notnormal health; and operating until a user of the apparatus determinesthat the analysis should be terminated, and intervenes to terminate theanalysis.

The term “a user of said apparatus” will often refer to a human operatorof the apparatus, but can also refer to a machine or system thatterminates operation of the apparatus automatically, including upondetection of a fault condition, such as a condition that could causeharm to a person, or upon detection of a condition where an unauthorizedperson is attempting to access patient information resident in theapparatus, for example in contravention of regulations such as theHealth Insurance Portability and Accountability Act of 1996 (hereinafter“HIPAA”). In addition, a user of the apparatus can in some embodimentsbe a medical data collection and/or recording system.

In some embodiments, the order of obtaining an image, obtaining a dataset indicative of a neurological disorder, and obtaining said additionalinformation about said person is not critical, and may be performed inany order that is convenient. For example, patient history and vitalsigns information may be collected before a person is tested with theapparatus of the invention. Data from other testing methods, such asPET, MRI, and cognitive impairment tests, may be obtained from testsperformed before or after the testing of a person with the apparatus.Where there is no requirement that a specified order of steps be adheredto, the present invention contemplates that the steps may be performedin any order, and even with intervening periods of delay, such as thetime needed for a person to move from one apparatus to another and forthe tests to be scheduled and performed, which apparata may be indifferent facilities or locations (such as an MRI imaging centerseparate from a venue where the apparatus of the invention is situated).

A Discussion of Alzheimers Disease

From a neurological perspective, the eye is a part of the brain. The eyedoes signal processing within the retina and has neurons that attachdirectly to the brain.

Ganglion cells lead from the retina to the lateral geniculate nucleus(LGN), which for the purpose of explanation will be called pathway #1(M). Pathway #2 (P!) leads from the LGN to the Visual Cortex (VC).Pathway #3 (P2) is a feedback loop from the VC back to the LGN. FIG. 12is a diagram showing the feedback loop associated with the retina, theLGN and the VC.

In glaucoma, the ganglion cells are damaged by an increase inintra-ocular pressure (IOP). One explanation of the damage is that thelamina cribrosa (LC) bends under the pressure and bends the ganglioncells in the outside of the LC. The ganglion cells coming from theperiphery of the retina lie at the periphery of the LC and are bent morethan those in the center of the LC, which are the ones coming fromcloser to the center of the retina. This extra bending causes extrastress on the ganglion cells, causing them to die early in glaucoma.This explanation accounts for the general observation that the typicalglaucoma patient goes blind in the periphery first and the loss ofvision narrows inward. Glaucoma also shows arcuate losses in clumps. Thelarge diameter ganglion cells (M cells and some of the P cells) are thefirst to die off because for large diameter cells there is more stresson those cells as they go through the tight openings in the LC.

An FDT device picks up these losses in M cells, in particular, sincethose cells respond to contrast sensitivity, the illusion used in theFDT. The FDT is discussed in more detail hereinafter. These losses arefound early in glaucoma because the large diameter M cells are the firstto die off in glaucoma and they do not overlap in their dendrites, sothere is no covering up by nearest M cell neighbors. After the ganglioncells start to die off, their corresponding areas in the LGN start todie off due to atrophy. Recent research showed loss in the LGN early inglaucoma corresponding to those areas where the lost ganglion cellsprojected. So, in the case of glaucoma, both ganglion cell loss and LGNloss appear to be caused by the increased IOP in the eye.

In Alzheimer's Disease (AD), there is no corresponding increase in IOP.In AD neurons degenerate due to other means. There is no bending of theLC and no loss of M cells early in AD from the LC. In normal individuals(also referred to as “normals”), all three pathways (M, P1, and P2above) are intact. The nerve signal goes from the retina across pathwayM to the LGN, then to the VC across P1, and finally back to the LGNacross P2. Since there are no losses in any of the three pathways, the80% feedback to the LGN from P2 correlates with what the LGN isreceiving from M. There are no apparent losses anyway in the system.

However, in early stages of AD, amyloid plaques and tangles attack theneurons in the brain. They may be found in P1, P2, the VC, or anycombination of those three. If they attack any of those three, then thesignal going back to the LGN across P2 does not correlate with what isgoing to the LGN from the retina across M. The brain has difficultycorrelating two signals that begin to become dissimilar as ADprogresses, as compared to signals that it expects to be similar (basedon years of normal neural activity). This response mimics a loss of Mcells when observed using FDT methods, though this may not be a realloss of M cells in early stages of AD. As the disease progresses, the Mcells likely atrophy because the LGN is not using the conflictinginformation from them. (There is a similar phenomena in the brain inambliopia where higher parts of the brain are confused by theconflicting signals coming from the two eyes, so the brain shuts off thesignal coming from one of the eyes causing that eye to atrophy over thefirst 6 years of life if the ambliopia is not corrected.)

One sees loss of gray matter in the brain in AD. Scientists have pickedthis up with both MRI and PET, as is discussed in more detailhereinbelow.

A lesion anywhere in the pathway can cause atrophy either upstream ordownstream of the lesion. One should expect to see loss of gray matterfirst where the lesion is, then upstream or downstream from the lesion.In late stages of AD, researchers have found amyloid plaques and tangleseven on the retina. The losses picked up by FDT when used with ADpatients are not necessarily like those in glaucoma. AD losses can occuranywhere in the visual field since the apparent losses correspond towhere the lesions are in the visual neuron pathway, which in principlecan correspond to anywhere in the visual field. Hence the visual fieldlosses in FDT are spottier than in glaucoma.

Similarly, the FDT can be used for multiple sclerosis (MS). It is knownthat MS affects neurons and that the effect comes and goes with time.There is apparent recovery of the cells at least in early stages of thedisease. One would therefore expect the FDT diagnosed areas of loss inthe visual field to move around the visual field over time, and perhapsto recovery temporarily. As the disease progresses to the point wherethere is a lot of loss on the retina, the areas of loss will remain lostand will not show temporary recovery.

The retina and brain do parallel processing to determine relativeposition of adjacent objects. In the case of dyslexia, this processingsomehow gets reversed and the subject mixes up the order of letters inwords or even the order of entire words. This too could show up as anapparent ganglion cell loss. Again, the apparent loss could be from theganglion cells or from the feedback to the LGN.

The FDT represents a device to measure early stages of neurologicaldisease and abnormalities, and to track changes over time. FDT has beenshown to provide earlier detection with less variability thantraditional visual field analysis as represented by the Humphrey HFA.FDT is non-invasive, fast, and accurate. It is easier to use than HFAand less expensive. The FDT can be a screener in the primary caredoctor's office to screen and track neurological disease. FDT can beextended for use with many neurological diseases, in addition toglaucoma. This makes it a good screening tool for primary care.

The present invention provides an improved FDT apparatus for screeningfor many neuro-degenerative diseases, including Alzheimer's,non-Alzheimer's dementia, Parkinson's, multiple sclerosis, maculardegeneration, ALS, diabetes, dyslexia, head trauma, and possibly others.

According to one feature of the invention, patients would be screened inthe doctor's office or in other settings such as a commercial screeningactivity to get a baseline reading. A primary care physician would theneither refer a patient to a specialist (if an abnormality is detected)or, if the screening results are initially within normal limits,watchfully wait for any progression by comparing results over time.

When a patient is referred to a specialist, the specialist mightprescribe the 2 hour cognitive tests and/or an MRI or PET scan for amore definitive diagnosis. All of these tests are expensive and timeconsuming, so it is important to weed out normals with the improvedapparatus prior to using these more expensive tests. The improvedapparatus can comprise an FDT2 62-zone test, an input port for aPanOptic retinal camera, and a programmable computer and softwarerecorded on a machine readable memory that when operating candifferentiate various neurological disorders. The standard of care willbe to screen for other neurological disorders beyond glaucoma and todifferentiate which disorder is present.

The present FDT (such as FDT Matrix) works well in its present form formeasuring apparent M cell losses in contrast sensitivity. In theimproved apparatus, additional sensitivity/specificity are gained byoptimizing the spatial frequencies, temporal frequencies, and/or colorof the patterns used to also detect changes more specific to P cells oreven K cells, i.e. all forms of retinal ganglion cells, projecting todifferent areas of the LGN.

The improved FDT device is expected to identify early stages of neuronalloss in the brain by picking up real losses of ganglion cells as well asapparent losses of ganglion cells as a result of the feedback loop tothe LGN caused by damage to neurons in other places in the brain.

Recent Findings Relating to Other Medical Technologies

Testing on 6 normal individuals, 6 individuals with mild cognitiveimpairment (MCI), and 6 individuals with AD are expected to show acorrelation between FDT measurements and early neuronal dysfunction(before neuronal loss or symptoms), using cognitive tests as a reference(e.g., “the gold standard”). It is further expected that MRI testresults will show differences in volume of the hippocampus andentorhinal cortex, which are both areas associated with early cognitivedysfunction. MRI is expected to demonstrate that early damage to thepathways between the lateral geniculate nucleus (LGN) and the visualcortex (VC) in the brain can be identified using FDT testing. Theattributes of the FDT are expected to include early or pre-symptomaticdiagnosis accomplished with a relatively inexpensive device thatperforms tests in a short time (for example, 4 minutes vs. 90 minutesfor a PET), which test is easily administered (compared to MRI or PETcertification), and is non-invasive (compared to PET which uses aradioactive tracer).

MRI is a high resolution (1 mm), non-invasive differentiator of softtissue, such as discriminating gray matter from white matter in thebrain. MRI can measure volume loss from atrophy caused by amyloidplaques, but cannot image the amyloid plaques themselves. In addition,MRI spectroscopy involves differentiating metabolites by their resonantfrequencies in a magnetic field gradient.

One may think of functional MRI (fMRI) as simply sequential MRI. Forexample, one can measure differences of oxygen level before and after astimulus. Oxygen level increases with increased activity. It locates theparts in the brain where a particular function or stimulus is processed.A stimulus that the brain responds to causes changes in synapses, whichincreases the blood flow to an area where activity is occurring, whichin turn increases the oxygen content, which causes a measurable changein the magnetic resonance image. Since fMRI measures brain activity, itcan determine viability of sections of the brain. One can usestimulation of selected retinal areas to probe regions of the visualcortex that respond. An fMRI image can be presented as a structural MRIimage with false color superposition to represent the level of activityin specific areas. However, fMRI cannot resolve such structures as 25micron long capillaries having 0.5 micron diameter. Rather, itintegrates the effects of all blood vessels in an area. One of thedifficulties associated with fMRI is the possibility that areas of thebrain can be accidentally stimulated.

Fluorodeoxyglucose positron emission tomography (FDG-PET) can be used tomeasure glucose metabolism. While its resolution is poor (3 to 8 mm), itis very sensitive to nano-molar quantities of neuro-transmitters andneuro-chemicals such as glucose and acetylcholene. It requires aradioactive tracer in the blood. It cannot be used to measure cognitivestate because one must wait 60 to 90 minutes for everything except theFDG trapped in the active tissue to wash out of the area. According tosome researchers, one can normalize a PET measurement by first doing astructural MRI to determine the amount of gray matter in each voxel.

Some researchers use radioactive carbon Pittsburgh compound B (PIB) as amarker that can be bound to amyloid in Alzheimer's (AD). Amyloid locatesbetween neurons and tangles within neurons. Amyloid concentrates inpre-frontal and temporal cortex, but not in the visual cortex and thehippocampus. It is believed, however, that tangles locate in thehippocampus and entorhinal cortex early in AD. Amyloid plaques appearbefore clinical detection of AD, which suggests that earlier detectionof AD can be accomplished by methods that permit the monitoring of suchamyloid plaques.

It has been found by researchers that hypo-metabolism in the lefthemisphere and visual cortex using PET can differentiate between frontaltemporal dementia (FTD) and AD. It is expected that FDT can alsodifferentiate FTD and AD.

Reduction in hippocampal volume has been shown to predict the conversionof MCI to AD. In addition, entorhinal cortex volume is 10% lower inpre-MCI individuals than in normal individuals and may therefore also bea predictor for conversion to AD. FDG-PET (glucose in cortex), amyloidimaging from PIB-PET, MRI measurement of hippocampal volume, or wholebrain atrophy appear to be predictors of cognitive decline and dementia.

Some researchers suggest that microglial action creates cytokines whenthe brain is injured and this damages the nerves. The use of C-PK11195bound to amyloid plagues in the thalamus and white matter hasdemonstrated earlier detection of amyloid than PET using PIB bound toamyloid, which appears to incorrectly suggest that the thalamus and VCare spared of amyloid in AD. While PIB used as a histologic stain onbiopsied material permits identification of both amyloid and tangles,PIB-PET identifies amyloid, but not tangles in gray matter in AD. Theposterior cingulated and frontal lobes retain more PIB in AD than inMCI, and more in MCI than in normals.

The progression of gray matter (cortex) loss in AD has been studied.Researchers have found 4 to 10% loss in hippocampal volume per year inAD compared to only 1.5% per year in normals.

MRI has been used to measure cortical thickness (gray matter) at manyindividual points in the brain. The cortical thickness varied from 1 to5 mm. Researchers have measured 0.02 mm/year loss in thickness due tonormal aging and 0.3 mm/year in AD. Researchers have also found loss inthickness of the VC, despite the fact that PET studies of amyloidsuggest that the VC is spared in early AD. Cortical thinning of inferiortemporal gyrate and para-hippocampal gyrate are suggested to give 100%sensitivity and 95% specificity in diagnosing AD.

It is known that higher magnetic fields, such 7T magnetic fields for MRIcan be used to see much finer structure in all parts of the brain. It isalso recognized that higher magnetic fields require more expensivemagnets, and can present certain risks (such as the risk that objectsthat are not carefully and adequately secured may become missiles thatare violently transported to the magnet).

Some researchers have used MRI to show tissue losses in the medialtemporal lobe (hippocampus and entorhinal cortex) in early MCI and AD,as well as changes in the shape of these areas.

Some researchers have found that neuronal loss correlates well withatrophy of hippocampus volume. On average, loss starts at age 53 andprogresses at different rates for normal (slowest), MCI, and AD(fastest) subjects. Decreases in hippocampal volume and in theentorhinal cortex can be identified in MRI . . . .

It is believed that the hippocampus is used in learning new information,such as associating a new name with a new face. Some researchers havefound that there is a decrease in hippocampus activity in MCI, followedby a significantly greater activity decease in AD with a total loss ofactivity in late AD. The medial temporal lobe of the cortex showed asimilar loss in activity in MCI, but showed a compensatory increase inactivity in AD, but no one understands why this is true. The three areasof the brain most responsible for brain activity of learning newmaterial such as a new name/face are the left pre-frontal cortex andboth sides of the hippocampus. Old information appears to be spread outacross the brain, rather than in those three specific areas.

Some researchers have found that the rates of change of volume of thehippocampus and entorhinal cortex accelerate with age, i.e. the loss isnot linear. Hippocampus loses about 4 to 6% per year in AD, 2.5% in MCI,and 1.5% in controls. Likewise, entorhinal loss is about 7% per year inAD and 1.5% in controls.

It is expected that there is a correlation of FDT measurements withhippocampus and entorhinal loss. It is expected that losses identifiedusing FDT methods are sensitive enough to show changes over time,including relatively short times such as one year. It is expected thatvolume alone of the hippocampus and entorhinal cortex will showdifferences between normal and severe AD.

According to some researchers, amyloid is present in all body fluids. Itis produced in glial cells in the central nervous system. ApolipoproteinE (“ApoE”) co-locates with amyloid in human brains and slows theclearing of amyloid from the central nervous system. Amyloid is presentat low levels for many years, and then starts to form in more abundance,forming plaques faster if ApoE is present than if not. Enzyme-linkedimmunosorbent assay (“ELISA”) can be used to test for the level of ApoEin a person's body.

Researchers have shown that hippocampal volume loss can predict whichindividuals will convert to AD. According to this research, brain volumeis reduced 0.2% per year in normal aging, which is much slower than thehippocampal loss in AD.

It is expected that correlations will be determined among FDTmeasurements and medial temporal lobe (hippocampal and entorhinalcortex) volume, volume and shape of LGN and VC (for example determinedby MRI), the progression of gray matter loss in the brain cortex of ADsufferers, and the early thinning of the cortex, particularly in theparahippocampus and VC.

FIGS. 13A-13B are diagrams showing the time evolution of response tostimuli using several testing procedures. In FIG. 13A, the horizontalaxis 1302 represents age in years of a person, and the vertical axis1304 represents cognitive ability, with greater ability represented bypoints that are more distant from the horizontal axis 1302. In FIG. 13Athere are sown three regions, labeled from left to right “Normal”,“MCI,” and “AD.” In FIG. 13A, a dividing line appears at an age ofapproximately 50 years between the “Normal” and “MCI” regions. Threecurves are also present in FIG. 13A. A first curve 1310 representsnormal behavior with respect to cognitive ability over time (e.g.,little or no diminution in cognitive ability over time). A second curve1312 represents the cognitive behavior with respect to time for a personwith mild cognitive impairment, and that curve shows some diminution incognitive ability with time. A person suffering from MCI may show somesymptoms of impairment, but there appears to be little or nor loss ofmental function. A person presenting with AD is expected to exhibit acognitive ability curve similar to 1314, in which the loss of cognitiveability is more severe. In AD sufferers, loss of mental function istypically observed. The significance of the curves in FIG. 13A is thatone may be able to provide an interpretive result indicating whether aperson has or is susceptible to getting MCI or AD. Similarly, otherrelationships can provide a similar interpretive result indicating thelikelihood that a person is susceptible to or the fact that a person isalready beginning to exhibit another disease.

In FIG. 13B, the axes 1302 and 1304 have the same significance as inFIG. 13A, and a curve 1314 for a typical person presenting with AD isshown. At the top of FIG. 13B, the arrows 1320-1334 are provided to showwhen in the development of a disease condition the various tests thathave been described are able to provide meaningful data. Arrow 1320represents a brain biopsy test, in which the tissue is stained with PIB.This test can be preformed meaningfully at any time, but it is invasive.Arrow 1322 represents cognitive tests, which can also be performed atany time, but which also are subject to some variability and may not beextremely accurate for small percentages. Arrow 1324 represents PETscans with PB3 to look for amyloid in the cortex. These tests becomeeffective at times after the clear inset of cognitive loss, possiblybecause by their expensive and invasive nature, they are not performedon people who appear to be normal. Similarly, fMRI tests as representedby arrow 1326 become effective at times after the clear inset ofcognitive loss. Arrow 1328 is representative of research results showingthat C-PK1119-PET tests can indicate the presence of amyloid in thethalamus and the white matter. Arrow 1330 represents MRI corticalthickness measurements which can be performed at any time, but which arealso expensive. Arrow 1332 represents MRI tests of hippocampal andentorhinal cortex volume. Arrow 1334 is representative of the FDT teststo discover neuronal dysfunction as described as embodiments of thepresent invention. As is seen, the tests according to the principles ofthe present invention can begin before a person becomes symptomatic, andbefore any appreciable loss of mental function has taken place.

FDT Apparatus

Some researchers believe that the FDT measures the loss of M cells ingeneral, but does not measure M.sub.y cell loss. FDT measures a“cortical loss of temporal phase discrimination”. FDT can be viewed as aprobe of contrast sensitivity of the magnocellular (“MC”) pathway. Ashas been expressed by researchers in the field, FDT measures the“reduced cortical sensitivity to the temporal phase of achromaticcounterphased gratings.”

FDT is a good screener for early glaucoma and a low-variability trendanalyzer. In glaucoma, FDT measures the loss of M cells, which lossappears to be caused by bending of large diameter cells by the displacedlamina cribrosa caused by elevated IOP and/or weak lamina cribrosastructure, starting in the periphery or more sporadically in scotomas.FDT can be used to measure the influence of these cells (or theirprogressive loss) on cortical phase discrimination downstream in thebrain.

In other forms of neurological disorders, the FDT measures a loss ofcortical phase discrimination, but not from M cell loss caused byincreased IOP and lamina cribrosa displacement. Instead, FDT ismeasuring the loss in cortical response due to other causes. Forexample, in Alzheimer's disease (AD), the apparent loss is likely comingfrom neuron loss somewhere in the pathway from lateral geniculatenucleus (LGN) to visual cortex (VC) and the feedback to the LGN (pathsP.sub.1 and P.sub.2 in FIG. 12). Amyloid plagues and tangles attackthese pathways in AD. The effect is one of apparent loss of M cells, butit is believed that the loss in the pathways may actually occur furtherback in the brain. The actual damage is to the neurons in the brain, butthe damage is manifest as a FDT-measured loss in contrast sensitivity.The visual cortex is still impaired in its ability to discriminatetemporal phase.

The actual damage from the plaques and tangles could be located anywherein the nervous system associated with vision, including the retina, theM cells, the LGN, path P₁, the VC, or path P₂. In early stages of AD,the plaques most likely occur in P₁, VC, or P₂. In later stages of AD,plaques have been found on the retina and, of course, in the brain assubstantiated by autopsies. It is almost immaterial where the damage isdone since the result is the same: the person suffering from these kindsof damage to the nervous system associated with vision scores anabnormal FDT test.

Parkinson's, multiple sclerosis (MS), and other neurological diseaseshave some similarity to AD, yet they are different and have differentunderlying features. The optimum parameters for measuring each disorderwith FDT may have different values, such as different special frequency,temporal frequency, number and size of zones, and color of the patternsthat are effective in disclosing the disease condition. Each of thesedisorders can be identified by the FDT test. It is important todifferentiate abnormal FDT responses from normal responses indicative ofnormal health. In addition, it is possible to differentiate amongdisorders through optimization of the FDT test and the analysis ofpatterns of loss. As an example, MS will show as more spotty losses inthe field. These losses will come and go until they stabilize at laterstages in the disease. By comparison, in patients experiencingParkinson's disease, the loss in vision is a more diffuse loss thaneither AD or MS. In addition, it is expected that correlation amongcognitive tests, MRI gray matter loss in the brain, and specificdiseases, such as AD, exist.

Many functions of electrical and electronic apparatus can be implementedin hardware (for example, hard-wired logic), in software (for example,logic encoded in a program operating on a general purpose processor),and in firmware (for example, logic encoded in a non-volatile memorythat is invoked for operation on a processor as required). The presentinvention contemplates the substitution of one implementation ofhardware, firmware and software for another implementation of theequivalent functionality using a different one of hardware, firmware andsoftware. To the extent that an implementation can be representedmathematically by a transfer function, that is, a specified response isgenerated at an output terminal for a specific excitation applied to aninput terminal of a “black box” exhibiting the transfer function, anyimplementation of the transfer function, including any combination ofhardware, firmware and software implementations of portions or segmentsof the transfer function, is contemplated herein.

While the present invention has been explained with reference to thestructure disclosed herein, it is not confined to the details set forthand this invention is intended to cover any modifications and changes asmay come within the scope of the following claims.

What is claimed is:
 1. An apparatus for performing multiple proceduresinvolving the eye, the apparatus comprising: a data collection apparatusfor collecting a data set corresponding to at least a portion of an eyeof a patient which is a real or apparent loss of ganglion cellsassociated with a neuronal loss in the brain, the data collectionapparatus configured to provide the data set that is indicative of atleast two neurological disorders including glaucoma and Alzheimer'sdisease, and further indicative of inappropriate responses to frequencydoubling contrast sensitivity patterns; and a data analysis module thatinterrelates the data indicative of said at least two neurologicaldisorders to provide an interpretive result.
 2. The apparatus as recitedin claim 1, further comprising a map generation module for generating amap indicative of the presence of a selected one of glaucoma, maculardegeneration, and inappropriate responses to frequency doubling contrastsensitivity patterns.
 3. The apparatus as recited in claim 1, furthercomprising a measurement module for measuring response that can beinterpreted as a real or apparent loss of ganglion cells associated witha neuronal loss in a brain with a selected one of Parkinson's diseaseand Alzheimer's disease.
 4. The apparatus as recited in claim 1, furthercomprising a measurement module for generating data indicative of thepresence of a selected one of dyslexia, multiple sclerosis, diabeticretinopathy, and optic neuritis.
 5. The apparatus as recited in claim 1,further comprising a data output module that reports the interrelateddata from the data set.
 6. The apparatus as recited in claim 1, furthercomprising a report module that reports the interpretive result.
 7. Theapparatus as recited in claim 1, further comprising a single outputmodule that reports the interrelated data from the data set and theinterpretive result.
 8. The apparatus as recited in claim 1, furthercomprising a superposition module for superimposing data obtained fromat least two data sets.
 9. The apparatus as recited in claim 8, furthercomprising a display configured for displaying the superimposed dataobtained from at least two data sets.
 10. The apparatus as recited inclaim 1, further comprising a memory for storing data.
 11. The apparatusas recited in claim 10, wherein the memory for storing data isconfigured to store and to selectively retrieve data from at least onedata set for determining changes in contrast sensitivity induced inresponse to an applied stress.
 12. The apparatus as recited in claim 11,where the applied stress is selected from the group consisting of intraocular pressure variation, blood pressure variation, oxygenconcentration variation, exercise, drug administration, administrationof insulin, and administration of glucose.
 13. The apparatus as recitedin claim 10, wherein the memory for storing data is configured toselectively retrieve data from at least one data set for trendinganalysis purposes.
 14. The apparatus as recited in claim 1, furthercomprising means for performing at least one objective eye-relatedinterpretive procedure relating to a neurological disorder.
 15. Theapparatus as recited in claim 1, wherein the data analysis module isconfigured to automatically determine a presence of an abnormality. 16.The apparatus as recited in claim 15, wherein said data analysis modulecomprises a scaling module for providing a scaled estimation of anextent of the abnormality.
 17. The apparatus as recited in claim 1,further comprising an information input module for inputting otherpatent-related information including at least one from the group oftonometer intraocular pressure, patient-history, family history, bloodpressure, vital signs, medication and pupillometry.
 18. The apparatus ofclaim 1 wherein said data set is indicative of an abnormality appearingto involve, at least in part, a retinal portion of the eye.
 19. Theapparatus of claim 18 wherein said abnormality actually involves, atleast in part, an abnormality of the brain.
 20. The apparatus of claim 1wherein said at least two neurological disorders are selected from thegroup consisting of glaucoma, Parkinson's disease and Alzheimer'sdisease.